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Advanced Drug Delivery Reviews 55 (2003) 667686www.elsevier.com/locate/addr
Pharmacokinetics in the newborna , b*Jane Alcorn , Patrick J. McNamara
aCollege of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, SK, S7N 5C9, Canada
bDivision of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA
Received 11 June 2002; accepted 22 January 2003
Abstract
In addition to differences in the pharmacodynamic response in the infant, the dose and the pharmacokinetic processes
acting upon that dose principally determine the efficacy and/or safety of a therapeutic or inadvertent exposure. At a given
dose, significant differences in therapeutic efficacy and toxicant susceptibility exist between the newborn and adult.
Immature pharmacokinetic processes in the newborn predominantly explain such differences. With infant development, the
physiological and biochemical processes that govern absorption, distribution, metabolism, and excretion undergo significant
growth and maturational changes. Therefore, any assessment of the safety associated with an exposure must consider the
impact of these maturational changes on drug pharmacokinetics and response in the developing infant. This paper reviews
the current data concerning the growth and maturation of the physiological and biochemical factors governing absorption,
distribution, metabolism, and excretion. The review also provides some insight into how these developmental changes alter
the efficiency of pharmacokinetics in the infant. Such information may help clarify why dynamic changes in therapeutic
efficacy and toxicant susceptibility occur through infancy.
2003 Elsevier Science B.V. All rights reserved.
Keywords: Development; Exposure; Human; Infant; Newborn; Pharmacokinetics
Contents
1. Introduction ............................................................................................................................................................................ 668
1.1. Pharmacokinetics as a determinant of plasma concentration and response........................ ................... .................... .............. 668
2. Absorption................... ................... .................... .................... .................... ................... .................... .................... ................. 669
2.1. Gastrointestinal absorption......................... .................... ................... .................... .................... .................... ................... . 669
2.1.1. Gastrointestinal secretions................................ .................... .................... ................... .................... .................... .... 6702.1.2. Gastrointestinal motility.......................... ................... .................... .................... ................... .................... .............. 670
2.1.3. Gastrointestinal metabolism and transport ................... .................... .................... ................... .................... .............. 671
2.2. Gastrointestinal first-pass effects ................... .................... .................... ................... .................... .................... ................. 671
3. Distribution........................ .................... .................... .................... ................... .................... .................... ................... ........... 672
3.1. Body composition and tissue perfusion .................... .................... ................... .................... .................... .................... ....... 672
3.2. Plasma protein binding .................... .................... .................... ................... .................... .................... ................... ........... 673
4. Elimination.................. ................... .................... .................... .................... ................... .................... .................... ................. 673
*Corresponding author. Tel.: 11-306-966-6365; fax: 11-306-966-6377.
E-mail address: [email protected] (J. Alcorn).
0169-409X/03/$ see front matter 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0169-409X(03)00030-9
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668 J. Alcorn, P.J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667686
4.1. Hepatic clearance............ ................... .................... .................... ................... .................... .................... .................... ....... 674
4.1.1. Intrinsic clearance ................. .................... .................... ................... .................... .................... ................... ........... 674
4.1.1.1. Cytochrome P450 enzyme-mediated metabolism ................... .................... .................... ................... ........... 674
4.1.1.2. Phase II metabolism............... .................... .................... ................... .................... .................... ................. 676
4.1.1.3. Consequences of variability in the postnatal maturation of phase I and phase II reactions............... ................. 678
4.1.2. Hepatic first-pass effects .................. .................... ................... .................... .................... ................... .................... . 6784.2. Renal clearance..... ................... .................... .................... .................... ................... .................... .................... ................. 678
4.2.1. Glomerular filtration.............. .................... .................... ................... .................... .................... ................... ........... 679
4.2.2. Renal tubular function .................. ................... .................... .................... ................... .................... .................... .... 679
5. Conclusions ............................................................................................................................................................................ 680
References ................... .................... .................... .................... ................... .................... .................... ................... .................... . 680
1. Introduction affects of postnatal development on drug and toxic-
ant pharmacokinetics in the newborn and early
Adult doses, even after adjusted for differences in infancy. The article describes the age-dependent
body weight, often lead to drastic consequences in changes in the physiological and/or biochemical
the newborn patient. Functional immaturity of phys- processes governing drug and toxicant phar-
iological processes and organ function predispose macokinetics. The article then extends these observa-
newborns to exhibit such disparate responses relative tions to discuss how developmental changes may
to the adult. With infant maturation, normal develop- lead to significant differences in absorption, dis-
ment may modify infant response to drug and tribution, metabolism and/or excretion between the
toxicant exposures. The full impact of developmental newborn, infant and the adult. Such discussion
immaturity, though, still remains unrealized as ex- should help explain the dynamic changes in thera-
emplified by the number of well-documented thera- peutic efficacy and toxicant susceptibility that occur
peutic misjudgments that continue even to this day through infancy.
[13]. We may mitigate future misjudgments through
a greater understanding of how development affects 1.1. Pharmacokinetics as a determinant of plasma
the factors that govern drug and toxicant response in concentration and responsethe newborn and young infant. Such knowledge may
help ensure safe exposures to therapeutic or inadver- Therapeutic and toxic responses generally corre-
tent compounds. late well with the plasma concentration of a com-
Pharmacokinetic and pharmacodynamic processes pound. Because of this correlation, plasma concen-
contribute to the significant differences in therapeutic trations may best indicate the potential safety and/or
efficacy and toxicant susceptibility observed between efficacy of the compound in the newborn and young
newborns, young infants and adults. With postnatal infant. This presumes that the pharmacological or
development, growth and functional maturation of toxic response is direct (i.e., related to corresponding
the biochemical and physiological factors governing serum concentrations), expected (i.e., similar to adult
pharmacokinetics may alter the processes of absorp- response) and quantitatively similar to adults (i.e.,
tion, distribution, metabolism and excretion. As well, similar pharmacodynamic parameters). A more dif-these developmental changes proceed along a con- ficult situation arises if the pharmacological or toxic
tinuum, at different rates and patterns, resulting in response is indirect (i.e., unrelated to serum con-
tremendous interindividual variability in infant phar- centrations), novel (a function of the developing
macokinetics. The dynamic and highly variable neonatal physiology/biochemistry) and quantitative-
character of postnatal maturation of infant phar- ly dissimilar to adults. Whether pharmacodynamic
macokinetic and pharmacodynamic processes may differences exist between pediatric population groups
have significant consequences on the way newborns and adults is largely unknown. Given this presump-
and infants respond to and deal with drugs. tion, two factors govern plasma concentrations, the
As its principal goal, this review discusses the size of the dose and the pharmacokinetic processes
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J. Alcorn, P.J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667686 669
of absorption, distribution, metabolism and excretion exhibit differences in toxicant susceptibility or thera-
acting upon that dose. The following equations peutic efficacy.
illustrate the influence of dose and pharmacokinetic In general, the combined effects of maturation of
processes on plasma concentrations of a compound, each pharmacokinetic process on the plasma levels
administered as either a multiple oral dose (Eq. (1)) of a given compound are not well understood.or as a single oral dose (Eq. (2)). Premature birth (gestational age ,36 weeks) and
underlying pathophysiology further complicate theFD relationship between plasma concentrations and re-]
t sponse and the age-related changes in phar-]]C5 (multiple dose) (1)Cl
S macokinetics. Premature infants exhibit more pro-
nounced anatomical and functional immaturity of theor organs involved in pharmacokinetic processes. The
extent to which premature infants differ from theCl SFk D
a ]2 t 2 k tS D s da full-term infant correlates directly with the degree ofV]]]S DC5 e 2 e (single dose)dt V k 2 ks dd a e prematurity [4]. This enhanced immaturity, as wellas any underlying disease state(s), may impede
(2) normal postnatal development of the processes of absorption, distribution and elimination. How thesewhere C is the average steady state plasma con-
and other factors may contribute to age-dependentcentration; F is the bioavailability; D is the dose; tpharmacokinetics in newborns and infants requiresis the dosing interval; Cl is the systemic clearance;
S
consideration. The proceeding discussion will sum-C is the plasma concentration at any time, t; k ist a
marize the available literature on the influence ofthe absorption rate constant; k is the elimination ratee
postnatal maturation on drug absorption, distribution,constant and is equal to Cl /V ; V is the volume ofS d dmetabolism and excretion principally in the full-termdistribution; and t is time.infant.According to Eqs. (1) and (2), larger doses (D)
result in higher plasma concentrations of an adminis-
tered compound. As well, these equations clearly
2. Absorptionillustrate the importance of absorption (indicated inthe F and k terms), distribution (indicated in the V
a d
Age-related differences in absorption relate toterm), and metabolism and excretion (indicated indevelopmental changes in those factors governingthe Cl and k terms) as determinants of plasmaS epassive or carrier-mediated transport across theconcentrations in the newborn and young infant.absorptive barrier. Systemic bioavailability becomesRapid changes in body size and composition, organan important consideration when compounds aresize and function, and maturation of the underlyingabsorbed from extravascular administration sites.physiological and biochemical processes that governThe absorptive characteristics of the compound andabsorption, distribution, metabolism, and excretionthe possible influence of first-pass effects may limitcharacterize the immediate postnatal period. Thesethe systemic bioavailability of the compound. Thisdevelopmental changes cause major age-related
may lead to lower plasma concentrations of thechanges in drug absorption, distribution and elimina-compound and reduced exposures.tion (metabolism and excretion), which may have a
significant impact on plasma concentrations and the2.1. Gastrointestinal absorptionresultant exposure outcomes. Additionally, matura-
tion is a dynamic process influenced by a plethora ofTable 1 summarizes the age-dependent anatomicalgenetic and environmental factors. The rate and
and physiological factors that may influence the ratepattern of maturation of each pharmacokinetic pro-and/ or extent of gastrointestinal absorption. De-cess may vary greatly among infants. This may resultvelopmental changes in one or any combination ofin marked interindividual variability in phar-these factors may explain the differences in absorp-macokinetics such that infants of similar age may
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670 J. Alcorn, P.J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667686
Table 1a
Age-dependent factors affecting gastrointestinal absorption and the resultant pharmacokinetic outcome relative to adult levels
Newborn Neonate Infant
(full-term) (1 day1 month) (1 month2 years)
Physiological factorGastric pH 13 .5 |Adult
Gastric emptying time Reduced (variable) Reduced (variable) Increasedb b
Intestinal surface area Reduced Reduced |Adult
Intestinal transit time Reduced Reduced Increased
Pancreatic and biliary function Very immature Immature |Adult
Bacterial flora Very immature Immature Immature
Enzyme/transporter activity Very immature Immature Approaching adult
Pharmacokinetic outcome
Rate and extent of absorption Variable Variable $Adult
Gastrointestinal first-pass effects Very reduced Reduced Approaching adult
aAdapted from Besunder et al. [7].
b
From Ref. [8].
tive characteristics between newborns and young pH in the newborn and young infant may involve
infants relative to the adult. The developmental enhanced bioavailability of weakly basic compounds,
pattern of these processes may be highly variable and but reduced bioavailabilities of weakly acidic com-
environmental factors (i.e., diet, concomitant drugs) pounds. This may explain the increased bioavail-
[5], genetic factors and underlying pathophysiology ability of ampicillin and penicillin G (basic drugs)
(electrolyte abnormalities, endocrinopathies, CNS [1719] and decreased bioavailability of phenobarbi-
disorders, gastrointestinal disease) [6] may poten- tal (acidic drug) [19,20] observed in young infants.
tially influence their postnatal developmental pattern. Certain compounds require pancreatic exocrine
In general, newborns exhibit a slower rate of and biliary function for adequate absorption. New-
absorption [6]. Age-dependent differences in the borns have immature pancreatic and biliary functionextent of absorption (bioavailability) remain largely at birth [21]. The levels of most pancreatic enzymes
unknown [8]. However, bioavailability (the fraction are significantly reduced [22], and bile formation,
of parent compound reaching the systemic circula- bile acid pool size (50% adult values), bile acid
tion) will likely change with postnatal age due to synthesis and metabolism, and bile acid intestinal
maturation of the processes governing absorption. absorption are all reduced in the newborn [2325].
Pancreatic and biliary function rapidly develop in the
2.1.1. Gastrointestinal secretions postnatal period [22,26]. A deficiency of bile salts
Gastrointestinal pH affects the absorption of weak- and pancreatic enzymes may result in a reduction in
ly acidic and basic organic compounds. At birth, the bioavailability of those drugs that require
newborns have an alkaline gastric pH (pH 68) solubilization or intraluminal hydrolysis (i.e., pro-
[9,10]. Gastric acid production increases over the drug esters) for adequate absorption.next 2448 h to achieve adult pH levels (pH 13)
[1113]. Following this initial burst of hydrochloric 2.1.2. Gastrointestinal motility
acid secretion, gastric acid production declines and Gastrointestinal motility may affect the rate and/
gastric acidity remains relatively low in the first or extent of drug absorption. In general, newborns
months of life [11,14]. Postnatal increases in gastric exhibit delayed gastric emptying rates and prolonged
acid production generally correlate with postnatal intestinal transit times relative to the adult [27,28].
age [15] and, on a per kg basis, adult levels are The full-term newborn infant demonstrates quali-
approached by 2 years of age [16]. tatively similar gastrointestinal motility patterns with
The pharmacokinetic consequences of high gastric the adult, but premature infants exhibit disorganized
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J. Alcorn, P.J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667686 671
and inefficient motility patterns [29,30]. In general, The developmental maturation of gastrointestinal
feeding triggers the postnatal development of gas- Phase II conjugation enzymes [4247] remains
trointestinal motility [5]. Reduced gastrointestinal unknown. However, b-glucuronidase activity of the
motility may have variable and unpredictable effects infant small intestine has been reported to exceed
on drug bioavailability in newborns and young adult activities by as much as 7-fold [48]. Thisinfants. In general terms, delayed gastric emptying enhanced b-glucuronidase activity may enable re-
may reduce the rate of drug absorption since the absorption of glucuronide drug conjugates. For drugs
small intestinal mucosa acts as the principal absorp- that undergo enterohepatic recirculation (i.e.,
tive site for most drugs. Alternatively, slower intesti- chloramphenicol, indomethacin) b-glucuronidase ac-
nal transit times may improve drug bioavailability tivity enhances their bioavailability.
due to longer retention times in the small intestine. The adult intestinal tract functionally expresses
The exact effect of developmental maturation of various members of the ATP-binding cassette and
gastrointestinal motility on drug bioavailability de- solute carrier transporter families [49,50]. These
pends upon the physico-chemical properties of the transporters may have an important impact on drug
drug and its interaction with the anatomical and absorption and bioavailability in the small intestine
physiological factors of the gastrointestinal tract. [51], but their exact role remains largely unknown.
The literature provides evidence of postnatal matura-
2.1.3. Gastrointestinal metabolism and transport tion of transport protein activities in other organ
Bacterial flora, principally concentrated in the systems [5258] suggesting gastrointestinal transpor-
ileum and colon [31], may influence the extent of ter function may also undergo a postnatal maturation.
drug absorption due to its influence on gastrointesti-
nal motility and ability to metabolize compounds 2.2. Gastrointestinal first-pass effects
[32]. At birth, infant gastrointestinal flora is very
immature and little information is available on the The gastrointestinal tract may play an important
effect of postnatal maturation of bacterial flora on role in the first pass metabolism of an orally adminis-
bioavailability [32,33]. In general, the bacterial flora tered compound [51]. Consequently, developmental
of the infant gastrointestinal tract approaches adult maturation of gastrointestinal metabolic and transport
populations by 4 years of age [34]. function may have significant consequences in gas-The proximal small intestine acts as the principal trointestinal first-pass effects and oral bioavailability.
absorptive site and site for significant first-pass In adults, some drugs undergo extensive metabolism
effects for many orally administered compounds. In in the gastrointestinal tract with a concomitant
the adult, the small intestinal mucosa functionally marked reduction in their oral bioavailability [59
expresses a limited number of phase I and phase II 61]. Immature gastrointestinal metabolic reactions
enzymes and their expression has led to significant may result in improved oral bioavailability as gas-
inter- and intra-individual variability in oral bioavail- trointestinal first-pass metabolism has less influence
ability [35]. Cytochrome P450 (CYP) 3A4 is the on the extent of absorption of such drugs. Converse-
predominant CYP enzyme expressed in enterocytes ly, some drugs are dependent upon carrier-mediated
[36,37], and CYP2C has the second highest expres- uptake systems in the intestinal mucosa for their
sion levels [37].Very low activity levels for CYP1A1 efficient absorption [62]. Immature development of[38] and CYP2D6 [35,39] were detected in intestinal transport function may lead to significantly reduced
microsomes. The maturation of CYP enzymes in the oral bioavailability.
intestinal mucosa remains largely uninvestigated. Some transporter proteins expressed in the intesti-
One study reported significantly lower CYP3A4 nal mucosa promote the active extrusion of drug
activity levels in intestinal microsomes from infants from the enterocyte back into the lumen of the
aged 03 months and a developmental increase in gastrointestinal tract after its absorption (i.e., MDR1)
activity with age [40]. As well, CYP3A7, the fetal [63,64]. These transporter proteins compete with
hepatic form of CYP3A, appears to lack expression absorption processes and may decrease the rate of
in extrahepatic tissues [41]. absorption and, potentially, the oral bioavailability.
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672 J. Alcorn, P.J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667686
The interplay between CYP3A4 and the active efflux postnatal period [65], while total body fat increases
transporter, MDR1, illustrates this concept [63,64]. progressively in the first months of life [66].
Again, immature development of these active efflux Age-related changes in total body water are pri-
processes may result in enhanced oral bioavailability. marily attributed to decreases in the relative per-
The exact effect of postnatal maturation on oral centage of extracellular water [65,67]. Extensivebioavailability will depend upon the interaction of tissue binding or partitioning into fat contribute to
the principal factors influencing bioavailability large V values. Polar compounds generally exhibit Vd d
(physico-chemical properties of the compound, equivalent to total body water or blood volumes.
physiology and anatomy of the gastrointestinal tract, Hence, age-related changes in fat, muscle and total
metabolic enzymes, transport processes) [51] and the body water composition may produce significant
degree of their postnatal maturation. quantitative changes in V and plasma concentrations.d
In newborns, the high relative proportion of total
body water and low proportion of fat results in a
general increase in V for water-soluble compoundsd3. Distribution
and a lower V for fat-soluble drugs relative to adults.d
Key pharmacokinetic parameters (i.e., clearancePostnatal changes in body composition, extent of and volume of distribution) are often normalized
binding to plasma proteins and tissue components,according to total body weight or body surface area.
and hemodynamic factors (cardiac output, tissueTherefore, it is critical to understand the develop-
perfusion and membrane permeability) may altermental changes in these body indices with postnatal
distribution characteristics in the developing infant.age, which is depicted in Fig. 1. While both total
The apparent volume of distribution (V ) provides ad body weight and surface area rise steadily during the
useful marker to assess age-related changes in drugfirst year of life, a considerable change in their ratio
distribution.occurs during the initial 3 months of life.
Developmental changes in V may also relate tod
3.1. Body composition and tissue perfusion postnatal enhancements in cardiac output, organ
blood flows and tissue perfusion, changes in mem-
Body composition may significantly affect drug brane permeabilities [7072] and maturation ofV . Changes in body composition correlate with both carrier-mediated transport systems [5558,7375],
d
gestational and postnatal age. Table 2 illustrates total and changes in tissue binding affinities or capacities
body water, total protein and total fat content in the since newborns and young infants have significantly
newborn, during infancy and in the adult stages.
Total body water decreases significantly in the early
Table 2
Developmental changes in body composition (reported as aa
percentage of total body mass)
Age Body Water Protein Fat
mass
(kg)
Newborn: full-term 3.5 74 11 14
4 months 7.0 61.5 11.5 27
12 months 10.5 60.5 15 24.5Fig. 1. Age-related changes in body weight, body surface areab
Adult 70 5560 (BSA) and the ratio of body weight to BSA. Data from the Center
aAdapted from Geigy Scientific Tables [66]. for National Health Statistics at the CDC [68] and Taketomo et al.
bObesity decreases the percentage of total body water. [69].
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J. Alcorn, P.J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667686 673
greater liver, kidney and brain masses relative to
total body mass [66,67,76].
3.2. Plasma protein binding
Postnatal development of plasma protein binding
may affect both the distribution and elimination of
compounds in the newborn and young infant. In
general, newborns and young infants exhibit larger
unbound fractions of a compound relative to the
adult. This may result in enhanced distribution intoFig. 2. General pattern of ontogeny for albumin (ALB) and alpha
tissues and a larger V . Age-related differences ind 1-acid glycoprotein (AAG) in newborns and infants. Data adapted
plasma protein binding affinity, plasma protein con- from [86] and are expressed as fraction of adult serum con-centration (mg/dl).centrations and availability of competing endogenous
compounds largely explain the differences in the
extent of binding.
Compounds bind principally to albumin and a -acid glycoprotein plasma concentrations and the1
alpha -acid glycoprotein. Albumin is the major fraction bound in the infant relative to the adult [86].1
plasma protein [77], and concentrations of alpha - Several endogenous substances (i.e., bilirubin,1acid glycoprotein, an acute phase reactant protein fatty acids) may compete for plasma protein binding
[78], fluctuate significantly in response to various sites [82,8789]. This competition may further re-
diseases, trauma or chemical insult [79,80]. In gener- duce the bound fraction of a compound in the
al, the newborn may exhibit lower binding affinities newborn, or cause displacement of the endogenous
of compounds (i.e., penicillin, phenobarbital, pheny- molecule from its protein binding sites. For instance
toin and theophylline) [81] to albumin and a -acid hyperbilirubinemia reduces the binding of the acidic1
glycoprotein [8284]. High unbound fractions may drugs ampicillin, penicillin, phenobarbital and
lead to significantly larger V values, and enhanced phenytoin [81,90]. Conversely, displacement of bil-d
renal clearance by glomerular filtration and hepatic irubin by drugs (i.e., sulfonamides) may enhance theclearance of low extraction ratio compounds in the risk for bilirubin encephalopathy [7]. Hepatic and
newborn. renal disease, hypoproteinemia due to malnutrition,
Developmental changes in plasma protein con- cystic fibrosis, burns, malignant neoplasms, surgery,
centrations have the most significant affect on the trauma and acidosis may further decrease plasma
extent of plasma protein binding in the young infant. protein drug binding due to decreased protein syn-
Total plasma protein levels are lower in the newborn thesis or competition for binding.
relative to the adult [85]. Lower plasma protein
levels reduce the plasma protein binding capacity in
the newborn. Fig. 2 illustrates the postnatal increase
in albumin and alpha -acid glycoprotein concen- 4. Elimination1
trations relative to adult levels. A strong correlationexists between the postnatal increase in plasma Systemic clearance provides a measure of the
albumin concentrations and the fraction bound [86]. efficiency of elimination and is often the most
This suggests adult binding characteristics (i.e., important pharmacokinetic determinant of plasma
unbound fraction) for a given compound and the concentrations and resultant response (see Eq. (1)).
ratio of infant and adult albumin concentrations may In general, hepatic and/or renal elimination path-
provide an estimate of infant unbound fractions for ways effect the removal of most compounds from the
that compound [86]. On the other hand, a weak body. These pathways are generally underdeveloped
correlation exists between the postnatal increase in and inefficient in the newborn. The various pathways
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674 J. Alcorn, P.J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667686
of elimination mature at different rates and patterns thione conjugation, and acetylation. Since most
of development and maturation to adult levels (ad- compounds are eliminated by more than one meta-
justed for body weight differences) is generally bolic pathway, postnatal changes in the efficiency of
achieved after the first year of postnatal life. Recent Phase I and Phase II reactions, differences in their
in vitro and in vivo probe substrate data have rate and pattern of development, and changes in theprovided important information on the maturation hepatocellular distribution and expression of Phase I
characteristics of hepatic and renal elimination mech- and Phase II enzymes [104] may have a significant
anisms (reviewed in Alcorn and McNamara, 2002) impact on the qualitative and quantitative charac-
[91]. This data provides the basis for the proceeding teristics of hepatic elimination in the newborn and
discussion. Additionally, for more in depth discus- developing infant. To predict the exact nature of
sion of the maturation of systemic clearance mecha- these consequences requires an understanding of the
nisms the reader is referred to excellent reviews by postnatal maturation of the individual hepatic meta-
Hakkola et al. [92], Ring et al. [93], Gow et al. [94], bolic pathways that mediate drug and toxicant re-
McCarver and Hines [95], Hines and McCarver [96], moval from the body.
de Wildt et al. [97], and Hayton [98].4.1.1.1. Cytochrome P450 enzyme-mediated metabo-
4.1. Hepatic clearance lism
The CYP enzymes represent a superfamily of
Hepatic blood flow, plasma protein binding and heme-containing enzymes [105]. CYP1A2, CYP2A6,
intrinsic clearance (defined as the maximal en- CYP2B6, CYP2Cs, CYP2D6, CYP2E1, and
zymatic or transport capacity of the liver) constitute CYP3A4/7 comprise the principal CYP enzymes
the physiological determinants of hepatic clearance important in drug and toxicant metabolism [106
[99,100]. Each of these determinants undergoes 108]. The rate and pattern of postnatal CYP enzyme
significant postnatal changes, and their maturation development may have a significant impact on
results in an enhanced capacity for hepatic elimina- therapeutic efficacy and toxicant susceptibility in the
tion of compounds with advancing postnatal age. newborn and developing infant. Interindividual dif-
ferences in their developmental patterns, genetic
4.1.1. Intrinsic clearance polymorphisms, and their induction/ inhibition po-Intrinsic clearance processes principally govern tential further complicate the role of CYP enzyme
the capacity of newborns to eliminate drug by the maturation on pharmacokinetics in the newborn and
liver. Although hepatocellular transport and biliary young infant.
excretion processes contribute to intrinsic clearance The postnatal maturation of CYP enzymes is
and are deficient at birth [74,101,102], hepatic evidenced in numerous literature reports of short-
biotransformation processes have the greatest impact ening half-lives and enhanced hepatic elimination of
on hepatic drug elimination in the developing infant. drugs in developing infants [109,110]. These studies
Phase I and Phase II reactions principally mediate suggest hepatic metabolic pathways undergo rapid
the metabolism of compounds in the developing postnatal development. Recently, in vitro studies
infant. Often a compound undergoes sequential have examined the maturation of individual CYP
metabolism with Phase I metabolic reactions preced- enzymes in age-dependent fetal and infant hepaticing Phase II metabolism [103]. microsomes [111115]. These studies corroborate
Of the phase I reactions, cytochrome P450 (CYP) the findings of the in vivo studies and have further
enzymes have the most important role in the elimina- elucidated the maturation characteristics of individ-
tion of most compounds. The postnatal maturation of ual CYP enzymes. As well, these studies have shown
other Phase I enzymes, such as the alcohol and the CYP enzymes mature at characteristic rates and
aldehyde dehydrogenases, esterases and the flavin- patterns of development and may be grouped accord-
containing monooxygenases, are reviewed in Hines ing to their general developmental pattern of activity
and McCarver, 2002 [96]. Important phase II re- [116]. Fig. 3 highlights the general pattern of CYP
actions include glucuronidation, sulfation, gluta- enzyme development as a fraction of adult levels
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J. Alcorn, P.J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667686 675
biotransformation and, in general, CYP enzyme-me-
diated metabolism improves with postnatal age and
generally approaches adult levels only after the first
year of life [117,120]. Table 3 summarizes the
maturation of individual CYP enzyme activity levelsbased upon in vitro determinations of CYP enzyme
activity in fetal, infant and adult age group hepatic
microsomes [111115].
4.1.1.1.1. Maturation of individual CYP
enzymes Fetal hepatic microsomes exhibit negligible
CYP1A2 enzyme activity [107,121,122]. CYP1A2
enzyme activity remains very low after birth and
significant in vitro activity is detected only by 13
months of age [112]. By the first year of lifeFig. 3. General pattern of postnatal development of the hepatic
CYP1A2 enzyme activity levels are only 50% adultclearance pathways in newborns and infants. Data adapted from
values and mature to adult activity levels sometime[91] and are expressed as fraction of adult clearance values after a year of age [112,120]. This pattern of(ml/min/kg). The general classification was adapted from Cres-teil, 1998 [116]. (CYP, cytochrome P450 enzyme; UGT, Uridine development explains the long half-life and low59-diphosphate-glucronosyltransferase; ST, Sulfotransferase; NAT, systemic clearance values of theophylline in the
N-acetyltransferase; GST, Glutathione-S-transferase).newborn [123]. Immature CYP1A2 enzyme develop-
ment prevents the biotransformation of theophylline
based upon enzyme activity values (normalized to resulting in prolonged half-lives in the newborn and
mg microsomal protein) from age-specific fetal, infant. Significant increases in theophylline systemic
neonatal and infant hepatic microsomes [116]. clearance values are observed only after 13 months
In vitro assessments have revealed significantly of age [123,124]. This pattern of theophylline clear-
lower levels of CYP enzyme protein and activity in ance with advancing postnatal age reflects the post-
the fetus (total CYP enzyme protein levels are one- natal development of in vitro CYP1A2 enzyme
third adult levels) [107,117,118]. These data are activity in the infant.consistent with literature reports demonstrating the Fetal livers fail to express CYP2A6 and CYP2B6
ability of the fetal liver to metabolize a variety of enzyme activity [107,122]. Otherwise, the postnatal
drug substrates [116,119]. For most CYP enzymes, development of CYP2A6 and CYP2B6 remains
though, fetal activity levels are only a small fraction largely unknown. Both CYP enzymes likely achieve
of adult activity levels, and parturition triggers their adult capacities only after the first year of life [120].
postnatal development [9294,116]. Consequently, Fetal and newborn (,1 week of age) livers
the newborn has a limited capacity for hepatic demonstrate very limited CYP2C enzyme activity
Table 3
In vitro cytochrome P450 (CYP) enzyme activity in age-specific fetal and infant hepatic microsomes as a fraction of adult activity (nmol21 21
min mg microsomal protein )CYP Fraction of adult activity
enzymeFetus ,24 h 17 d 828 d 13 m 312 m 115 y
1A2 0.05 0.12 0.10 0.20 0.39 0.46 1.10
2C 0.02 0.03 0.42 0.29
2D6 0.04 0.04 0.09 0.24
2E1 0.21 0.31 0.36 0.46 0.39 0.80
3A4 0.03 0.08 0.13 0.29 0.34 0.43 1.08
3A7 5 9.5 13 6 3 2
Adapted from Refs. [111115].
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676 J. Alcorn, P.J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667686
[118,125]. Within the first month of postnatal life, activity and express limited CYP3A4 enzyme activi-
CYP2C enzyme activity surges to 50% adult levels ty (|10% adult levels) [111,122]. CYP3A7 enzyme
[114,117]. After this surge of activity, CYP2C activity levels peak 1 week after parturition, then
enzyme activity levels decline slightly for the first declines significantly during the first year of life
year of life and adult levels are reached sometime [111,120]. Adult livers may express only 10% fetalafter 1 year of age [114,117,120]. As a substrate of levels [111,132]. During the postnatal period, activi-
the CYP2C enzyme subfamily, diazepam metabolite ty levels of CYP3A4 enzyme increase concomitantly
urinary levels are consistent with the in vitro pattern with the decreases in CYP3A7 enzyme activity
of CYP2C enzyme development. Newborns exhibit [111]. CYP3A4 enzyme activity reaches 3040%
very low urinary diazepam metabolite levels [114]. adult levels by 1 month of age and adult levels by 1
However, diazepam urinary metabolite levels in- year [111,120]. The pharmacokinetic consequences
crease significantly in infants greater than 1-week- of this postnatal developmental switch from
old [114]. Thereafter, metabolite levels remain rela- CYP3A7 to CYP3A4 remain largely unknown since
tively stable in children up to 5 years of age [114]. the substrate profile of CYP3A7 enzyme has re-
Fetal livers may express very low levels of ceived limited investigation. However, some studies
CYP2D6 enzyme activity [107,113]. A dramatic suggest newborns and adults will exhibit significant
increase in CYP2D6 activity occurs in the immediate differences in their capacity to eliminate known
postpartum period. By the first month of life, CYP3A4 enzyme substrates. For example, premature
CYP2D6 enzyme activity levels reach |30% adult and full-term newborns eliminate the CYP3A4 en-
levels [113], and CYP2D6 maturation may be com- zyme substrate, midazolam, with poor efficiency
pleted by 1 year of age [120]. In vivo assessment of [133]. A 5-fold increase in the elimination efficiency
the hepatic clearance of CYP2D6 substrates is of midazolam occurs by 3 months of age [134].
lacking in the newborn and young infant. These data suggest midazolam is not an efficient
Fetal hepatic microsomes may express low levels CYP3A7 enzyme substrate.
of CYP2E1 enzyme activity [126]. Parturition trig-
gers a dramatic increase in CYP2E1 enzyme activity 4.1.1.2. Phase II metabolism
within the first 24 h of life [115]. CYP2E1 enzyme Phase II or conjugation reactions contribute sig-
activity levels achieve 50% adult levels by 13 nificantly to the elimination of a wide variety ofmonths of age and development is essentially com- exogenous and endogenous compounds. Glucu-
plete after 1 year of age [115]. ronidation, sulfation, acetylation, glutathione conju-
CYP3A subfamily is the most abundantly ex- gation, comprise the most important Phase II path-
pressed CYP enzyme in the liver [106,127]. ways in drug and toxicant metabolism. In general,
CYP3A4 enzyme is the principal enzyme of the adult changes in the expression patterns of the different
liver [106], while fetal livers predominantly express Phase II enzymes or changes in their catalytic
CYP3A7 enzyme [111,128,129]. Although CYP3A4 efficiency may occur with development. Such
and CYP3A7 enzymes exhibit 95% similarity in their changes may have important consequences on the
nucleotide sequences [130], important differences in elimination of compounds in the newborn and young
substrate specificities exist between these two infant. In general, inefficient conjugation capacity of
CYP3A enzymes [107,111,131]. Few studies have the newborn will result in a significant reduction inexamined the substrate profile of CYP3A7 enzyme. the ability of the newborn to eliminate both exogen-
The ability of fetal livers to metabolize a wide ous and endogenous compounds. Table 4 and Fig. 3
variety of substrates [119] suggests CYP3A7 enzyme summarize the known maturation patterns of im-
also may metabolize a wide range of substrates and portant Phase II enzymes. For a more in depth
demonstrate some substrate overlap with CYP3A4 discussion of the development of Phase II metabolic
enzyme. pathways, the reader is referred to the review by
Total CYP3A enzyme protein levels remain rela- McCarver and Hines [95].
tively constant throughout development [111]. Fetal 4.1.1.2.1. Maturation of individual conjugation
livers demonstrate high levels of CYP3A7 enzyme reactions The uridine 59-diphosphate-glucrono-
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Table 4 capacity to eliminate morphine, and adult levels wereMaturation patterns of phase II enzymes achieved by 630 months of age [146,147].Phase II enzyme Maturation pattern Sulfotransferases (ST) consist of a number of
individual enzymes and have substrate specificitiesUGT Fetal livers exhibit limited enzyme activity;
activity |25% adult levels at 3 months; that demonstrate significant overlap with the UGTmaturation is isoforms specific; adult enzymes [148]. Although changes in activity of theactivity levels achieved by 630 months. individual ST enzymes with development occur, the
data on their development is limited and confusing.ST Fetal livers exhibit significant activity;
In general, fetal, newborn and infant livers expressmaturation is isoform specific.significant ST activity, and sulfate conjugation is a
GST Fetal livers exhibit significant activity; relatively efficient pathway at birth [149151]. Con-maturation is isoform specific; total sequently, the newborn and young infant may elimi-activity remains stable throughout infancy.
nate ST enzyme substrates very efficiently. For
instance, the ST and UGT enzyme substrate ritod-NAT Fetal livers exhibit low activity; lowactivity at birth through the first months of rine, a b -adrenoceptor agonist, underwent extensive
2
life; adult levels achieved after 1 year of age. sulfate conjugation in infants [149]. The study
demonstrated no age-related differences in the over-UGT, Uridine 59-diphosphate-glucronosyltransferase; ST,Sulfotransferase; NAT, N-acetyltransferase; GST, Glutathione-S- all systemic clearance of ritodrine, only quantitativetransferase. differences in metabolite levels (glucuronide conju-
gates and sulphate conjugates) between infants and
adults [149].
syltransferases (UGT) enzymes consist of two Glutathione-S-transferases (GST) represent a
families, UGT1 and UGT2, containing more than 18 superfamily of dimeric enzymes responsible for the
different enzymes [97,135]. More than one UGT detoxification of a number of potentially toxic drug
enzyme may participate in the metabolism of a single or drug metabolites [152]. Five different subunit
substrate [136,137], and the maturation of UGT classes (m, a, u, p and z) of GST enzymes have
enzyme capacity is isoform specific [97,138]. Conse- been classified [152,153]. As with the ST enzymes,
quently, the developmental rate and pattern of in- the GST enzymes demonstrate age-related expressiondividual UGT enzymes may explain the tremendous of individual enzymes in the liver [154156]. For
variability reported in the glucuronidation capacity of example, preterm newborn livers exhibited 60%
newborns and infants. In their review on the de- greater activity towards chloramphenicol than fetal
velopmental maturation of glucuronidation capacity livers, but showed similar activity levels towards
in the infant, de Wildt et al. suggest the clinical chlorodinitrobenzene [157]. However, the literature
relevance of the development of individual UGT remains sparse and presents conflicting information
enzyme capacity in infants remains unclear [97]. with respect to individual enzyme development
As a whole, newborns and young infants demon- [156,157]. In general, though, GST activity is rela-
strate inefficient glucuronidation capacity relative to tively well-developed in the newborn and infant, and
the adult [139141]. Fetal livers exhibit limited UGT total GST activity may remain relatively stable
enzyme activity [142,143]. Fetal hepatic microsomes throughout development [158]. The clinical signifi-(1527 weeks gestation) catalyzed morphine glucu- cance of the quantitative and qualitative differences
ronidation at only 1020% the efficiency of adult in the developmental expression of individual GST
hepatic microsomes [144,145]. Parturition triggers an enzymes remains unknown, but may have important
increase in UGT enzyme activity and UGT enzyme implications in toxicant susceptibility.
activity achieves |25% adult levels by 3 months of N-acetyltransferases (NAT) consist of two en-
age [143]. The in vivo postnatal elimination pattern zymes, NAT1 and NAT2, and NAT2 demonstrates
of the UGT enzyme substrate, morphine, is con- polymorphic activity [159161]. Very limited data
sistent with the in vitro studies. Premature and full- exists on the developmental expression of NAT1 and
term infants have a markedly reduced and variable NAT2 enzyme activity. Fetal livers express activity
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678 J. Alcorn, P.J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667686
towards several NAT enzyme substrates, but at much assessment of elimination capacity in the newborn
lower levels than the adult [47,162]. Consequently, and young infant.
the newborn exhibits a limited capacity to acetylate
substrates. The acetylation status of the infant may 4.1.2. Hepatic first-pass effects
reflect adult levels only well past the first year of life For many drugs subject to first-pass effects,[163165]. hepatic metabolism results in a significant reduction
in the oral bioavailability of a compound. Postnatal4.1.1.3. Consequences of variability in the postnatal maturation of metabolic enzyme pathways and hepa-
maturation of phase I and phase II reactions tocellular transport systems may result in significant
Many compounds undergo multiple routes of differences in the oral bioavailability of compounds
metabolism. Quantitative and qualitative differences in the newborn and young infant relative to the adult.
in the developmental expression profiles of metabolic For all orally administered compounds, plasma pro-
pathways of the liver may modify the rate and tein binding and intrinsic clearance determine the
pattern with which newborns and infants eliminate extent of parent drug bioavailability [99]. Newborns
compounds throughout development. These inter- generally exhibit lower plasma protein binding ca-
individual differences may lead to altered metabolite pacities. Higher unbound fractions of an absorbed
profiles as the relative contribution of the different compound may theoretically enhance oral clearance
routes of metabolism may vary with infant age. and result in lower oral bioavailability of the com-
Differences in metabolite profiles become significant pound. For most drugs, intrinsic clearance has the
when a particular metabolite has pharmacological or most important effect on bioavailability. At birth,
toxicological activity. Consequently, the rate, pattern immature Phase I and Phase II metabolic enzyme
and extent of metabolic pathway maturation are pathways and hepatocellular transport processes may
important considerations in the pharmacokinetic significantly reduce the extent of first-pass hepatic
consequences of postnatal maturation of hepatic metabolism of an absorbed compound. Inefficient
clearance pathways. Interindividual differences in the hepatic metabolism in the newborn may cause
rates and patterns of individual elimination pathway enhanced oral bioavailabilities relative to the adult.
maturation may largely explain the tremendous Maturation of the hepatic metabolic pathways will
interindividual variation observed in the capacity of result in age-related reductions in oral bioavail-newborns and infants to eliminate drugs. Superim- ability. As with hepatic clearance, interindividual
posed upon the interindividual variability in metabol- differences in the rate and pattern of metabolic
ic enzyme maturation is the influence of metabolic enzyme pathway maturation may cause significant
enzyme induction and/ or inhibition. In utero and/ or interindividual variation in oral bioavailability during
postnatal exposure to certain exogenous or endogen- postnatal development. Hence, postnatal maturation
ous compounds may cause rapid enzyme induction of hepatic metabolism may greatly influence thera-
or inhibition in the fetus, newborn and infant [166]. peutic efficacy and toxicant susceptibility because
This will further exacerbate the variable rate and hepatic metabolism may determine the both the oral
pattern of enzyme maturation. For example, new- bioavailability of a compound and the efficiency with
borns treated concomitantly with barbiturates, a which the newborn or young infant may remove that
CYP2C inducer [114], exhibited a marked reduction compound from the body.in diazepam (a CYP2C substrate) half-lives (t 5
1 / 2
1861 h) as compared with newborns treated with 4.2. Renal clearance
diazepam alone (t 53162 h) [114,167]. Further-1 / 2
more genetic polymorphisms in CYP2D6, CYP2C9, Renal clearance mechanisms include glomerular
CYP2C19, CYP2E1, UGT and NAT [168] may filtration (GFR), tubular secretion and tubular re-
further enhance the interindividual variability in drug absorption. At birth, these renal clearance mecha-
elimination characteristics observed in infants. Poly- nisms are incompletely developed and renal elimina-
morphisms in drug metabolism and the potential for tion capacity of the newborn is significantly compro-
enzyme induction and/or inhibition complicate any mised [169171]. During late gestation and early
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J. Alcorn, P.J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667686 679
postnatal development profound anatomical and average and a slower pattern of GFR development
functional changes in the kidney greatly enhance during the first 12 weeks postpartum as compared
renal elimination efficiency in the first few months of with the full-term infant [4,183,196]. With comple-
life [172,173]. Renal functions demonstrate a rapid tion of nephrogenesis and maturation of glomerular
maturation and generally reach adult levels before 1 function, enhancements in GFR in the preterm infantyear of age [174176]. Maturation of glomerular will proceed at the same rate as full-term infants
filtration and renal tubular functions proceed at [183]. However, even by 5 weeks of age the absolute
different rates and patterns resulting in marked value for GFR remains lower in preterm infants
interindividual variability in renal elimination ef- [183]. This functional delay in GFR in preterm
ficiency. infants is an important consideration in the estima-
The anatomical and functional development of the tion of an infants capacity for renal elimination.
kidney continues throughout gestation into the early Interestingly, Fig. 4 illustrates infant GFR, on an
postnatal period. Nephrons increase in number until ml/ min/ kg basis, is roughly comparable to the adult
nephrogenesis is completed at 36 weeks of gestation [185]. This implies adult renal clearance values
[172,173,177,178]. Prior to 36 weeks gestation, then, normalized to a body weight may reasonably predict
changes in renal function principally correlate with infant renal clearances on a body weight basis.
increases in the number of nephrons [179181].
Incomplete nephrogenesis in the pre-term newborn 4.2.2. Renal tubular function
will compromise glomerular and tubular function At birth, the renal tubules exhibit significant
[182]. Functional maturation and growth processes anatomic and functional immaturity [197]. Incom-
explain the changes in renal elimination capacity in plete anatomical development of renal tubules com-
the full-term infant [98,172]. In general, postnatal promises both passive reabsorption [188,198] and
functional maturation of the kidney is associated active secretion and reabsorption processes [199
with enhancements in renal blood flow, improve- 201]. In addition to limited tubular size and func-
ments in glomerular filtration efficiency and the tional maturity, poor peritubular blood flow, reduced
growth and maturation of renal tubules and tubular urine concentrating ability, and lower urinary pH
processes [98]. values further compromise renal tubule function in
the newborn [202]. In general, renal tubular growth4.2.1. Glomerular filtration processes, maturation of renal tubular transport sys-
During the fetal stages, GFR capacity is signifi- tems, and redistribution of blood flow to the secret-
cantly reduced [172]. Parturition triggers enhance- ory areas of the kidney account for the enhancements
ments in both cardiac output and renal blood flow
and a dramatic decrease in renal vascular resistance
and a redistribution of blood flow within the kidney
[172,183185]. These hemodynamic changes cause a
rapid increase in GFR during the early postnatal
period [4,171,186190]. At birth, GFR, normalized
to body surface area, in the full-term infant is 10152
ml/ min/ m [169,171], but increases to 2030 ml /2min/ m within the first 2 weeks of life [171,191]. By
6 months of age, infant GFR, normalized to body
surface area has approached adult levels (73 ml/2
min/m ) [192]. Rapid improvements in GFR result
in rapid enhancements in the renal clearance ofFig. 4. General pattern of postnatal development of the renalcompounds principally eliminated by GFR.clearance pathways in newborns and infants. Developmental
Postnatal improvements in GFR correlate withchanges in glomerular filtration rate (GFR), renal tubular secretion
gestational age rather than postnatal age [4,193 (TS) and renal blood flow (Q ). Data adapted from [98] and areR
195]. Premature infants exhibit lower GFR values on expressed as fraction of adult clearance values (ml/min/kg).
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680 J. Alcorn, P.J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667686
in renal tubular function during postnatal develop- tional immaturity of absorption, distribution, metabo-
ment [171,187,203]. As the infant develops, matura- lism and/or excretion processes contribute to the
tion of renal tubular function generally exhibits a disparate responses observed between newborns,
more protracted time course than GFR. This infants and adults. Premature infants present a fur-
produces a functional glomerulotubular imbalance ther complication as the anatomical and functionaluntil renal tubule maturation is completed by 1 year immaturity of the organs and other biochemical and
of age [204,205]. physiological processes involved in drug phar-
Numerous protein carrier systems mediate active macokinetics is further exacerbated. An assessment
renal excretion and reabsorption. Their postnatal of the therapeutic efficacy or toxicant susceptibility
development at the renal tubular epithelium and their of a newborn to an exposure will require a careful
impact on renal elimination efficiency in the new- consideration of the developmental aspects of phar-
born and infant remains largely unknown. Func- macokinetic processes. In general, the combined
tionally, the kidney exhibits a reduced capacity to effects of age-related changes in each phar-
excrete weak organic acids like penicillins, sulfon- macokinetic process on plasma levels of a compound
amides, and cephalosporins [200,201]. Newborn are poorly understood. Clinical studies encompassing
kidneys excrete p-aminohippurate (PAH), a substrate newborns and infants within narrow postnatal age
for the organic anion transporters, at 2030% adult groups are needed to enhance our understanding of
levels [187], and adult excretion levels are ap- the pharmacokinetic and clinical consequences of
proached by 78 months of age [176]. Premature postnatal maturation of absorption, distribution, me-
and full-term infants excrete furosemide, a PAH tabolism and excretion processes. Such information
transport pathway substrate, slowly with plasma half- will help to establish more effective guidelines to
lives of 19.9 and 7.7 h, respectively, as compared predict an exposure outcome in a newborn or young
with 0.5 h in the adult [206,207]. In utero or infant infant and to ensure safe exposures to therapeutic or
exposure to certain agents may induce or inhibit inadvertent compounds.
renal tubular transport functions [174]. Transport
induction or inhibition may compound the variability
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