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DISTRIBUTION OF DISTRIBUTION OF XENOBIOTICSXENOBIOTICS
I. GENERAL PRINCIPLES II. CNS DISTRIBUTION III. MATERNAL-FETAL DISTRIBUTION IV. DISTRIBUTION INTO BREAST MILK
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I. GENERAL PRINCIPLES
Distribution:
The reversible transfer of xenobioticsfrom one location in the body to another
A. Extent of Distribution
Determined by:• partitioning across various membranes•binding to tissue components•binding to blood components (RBC, plasma protein)•physiological volumes
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Components of Total Body Water
Vascular
3 L
4% BW
Extravascular
9 L
13% BW
Extracellular
Intracellular
28 L
41% BW
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How can we measure the extent of distribution?
Apparent volume of distribution (Vd)
ionconcentrat drugplasma
body in drug ofamount dV
VOLUME OF DISTRIBUTION FOR SOME DRUGS
DRUG Vd (L)cocaine 140clonazepam 210amitriptyline 1050amiodarone ~5000
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What is the volume of water inthe beaker?
ionconcentrat
amountVolume
L1mg/L 10
mg 10 Volume
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What is the volume of water inthe beaker?
ionconcentrat
amount Volume
LLmg
mg10
/1
10 Volume
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Plasma Extracellular water
Plasma protein Tissue proteindrug
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Adverse Reactions to Phenytoin as a Function of Serum Albumin
Concentration
0
2
4
68
10
12
14
<2.5 2.5-2.9 3.0-3.4 3.5-3.9 >3.9
Serum albumin (g/dl)
% o
f pts
wit
h ad
vers
e re
acti
ons
Data from: Boston Collaborative Drug Surveilliance Program. Clin Pharmacol Ther 14:529-532, 1973.
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I. GENERAL PRINCIPLESA. Extent of DistributionB. Rate of Distribution
0
5
10
15
20
25
30
0 5 10 15
Time, min
Tis
su
e A
mt
(mc
g/g
)Thiopental
Pentobarbital
Brain concentrations of thiopental and pentobarbital after iv administrationin the rat. Adapted from: Principles of Drug Action - The Basis of Pharmacology, p. 264, 1990.
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Time course of thiopental in blood and tissues afterintravenous administration.
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II. CNS DISTRIBUTIONThree compartments in the CNS:•blood•brain•cerebrospinal fluid (CSF)
Three anatomical barriers•blood-brain barrier•blood-CSF barrier•CSF-brain barrier
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Reproduced from: Pratt WB, Taylor P. Principles of Drug Action: The Basis of Pharmacology.
3rd edition, 1990, p. 257.
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Mechanisms of Blood-Brain Barrier Mechanisms of Blood-Brain Barrier BiotransportBiotransport
From: Tsuji A. Specific mechanisms for transporting drugs into brain, In: From: Tsuji A. Specific mechanisms for transporting drugs into brain, In: The Blood-Brain Barrier The Blood-Brain Barrier and Drug Delivery to the CNSand Drug Delivery to the CNS. Begely DJ, Bradbury MW, Kreuter J. Marcel Dekker, New York, 2000.. Begely DJ, Bradbury MW, Kreuter J. Marcel Dekker, New York, 2000.
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Transport Systems for the CNS
Carrier-Mediated glucose, amino acids, lactic acid, thryoid hormone nucleosides
Receptor-Mediated angiotentin II, insulin, transferrin
Plasma Protein-Mediated corticosteroids, androgens, propranolol, estradiol bupivicaine
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Means by which xenobiotics may gainentry to the CNS:
•appropriate physiochemical properties•utilize an existing transport•direct administration into the CNS•disruption of the blood-brain barrier
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Effect of co-administration of methyldopa and neutralamino acids on brain methyldopa content in rats. From: Markovitz DC, Fernstrom JD. Science 197:1014-1015, 1977.
HO
HO
COOH
CH3H2N
methyldopa
HO
HO
COOH
NH2
L-dopa
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02468
10
0 50 100Time, min
Bra
in M
eth
yldo
pa
(mcg
/g)
Control
+ Neutral Amino Acids
Effect of co-administration of methyldopa and neutralamino acids on brain methyldopa content in rats. From: Markovitz DC, Fernstrom JD. Science 197:1014-1015, 1977.
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Effect of co-administration of methyldopa and neutralamino acids on brain methyldopa content in rats. From: Markovitz DC, Fernstrom JD. Science 197:1014-1015, 1977.
0
5
10
0 50 100
Time, min
Bra
in M
eth
yld
op
a (m
cg/g
)
Control + Acidic Amino Acids
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0
10
20
30
40
50
Indinavir Nelfinavir Saquinavir
mdr1a (+/+) mdr1a (-/-)
Role of P-glycoprotein determining brain content of protease inhibitors. Data from: Kim et al. J Clin Invest 101:289-294, 1998.
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Mother Fetus
Polar drug
Non-polar drug Non-polar drug
Polar metabolite Polar metabolite
III. MATERNAL-FETAL DISTRIBUTIONIII. MATERNAL-FETAL DISTRIBUTION
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Maternal and Fetal Concentrations of Tubocurarineand Thiopental After IV Maternal Administration inHumans. Data from: Cohen EN. Anesth Analg 41:122, 1962.
Time 5 6 9 11
TubocurarineMaternal Fetal 3.0 0.0 3.2 0.0 1.1 0.1 2.1 0.1
ThiopentalMaternal Fetal 8.5 5.5 8.0 3.5 4.8 2.5 2.0 1.2
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Factors that may influence placental transfer
Factor Effect
Placental blood flow increased delivery of drugto placental membrane
Molecular size of drug decreased transfer as sizeincreases
impermeable to drugs MW>1000permeable to drugs MW<600
Lipid solubility of drug increased transfer as lipidsolubility increases
pKa of drug ion trapping on either side
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IV. DISTRIBUTION INTO BREAST MILK
MS
mun
m
punp
ff
ffPM
M/P - milk to plasma concentration ratioS/M - skim to whole milk concentration ratiofp - unbound fraction in plasmafm - unbound fraction in milkfun - unionized fraction in respective fluid
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Concentration-time profile for cimetidine in serum ()and breast milk (O) after a single dose in a lactating female. Reproduced from Clin Pharmacol Ther 58:548-555, 1995.