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Drug Metabolism
S.P. Markey
Laboratory of Neurotoxicology
NIMH, NIH
Nov. 14, 2002
Evolution of Drug Metabolism As a Science
Post WWII Pioneers • R.T. Williams – Great Britain
– 1942, worked on the metabolism on TNT with regard to toxicity in munitions workers; due to the war he assembled teams to work on metabolism of sulfonamides, benzene, aniline, acetanilide, phenacetin, and stilbesterol
– Developed concept of Phase 1 & Phase 2 Reactions. • Biotransformation involves metabolic oxygenation,
reduction, or hydrolysis; result in changes in biological activity (increased or decreased)
• Second phase, conjugation, in almost all cases resulted in
detoxication.
Evolution of Drug Metabolism As a Science
Post WWII Pioneers • B.B. Brodie, U.S.
– NYU and Laboratory of Industrial Hygiene, NYC 1949 – Metabolic fate of acetanilide and phenacetin in man (with J. Axelrod)
– 1950s, NIH – pioneering studies on all aspects of drug metabolism; esp. reserpine, serotonin;hexobarbital tolerance
– 1952 – R.T. Williams spent 6 months at NIH; subsequently many students went between both labs (Dick Adamson, Jim Gillette, and Sidney Udenfriend)
– 1950s, Brodie lab developed the spectrophotofluorimeter (R. Bowman)
Drug Metabolism
Hepatic microsomal enzymes (oxidation, conjugation)
Extrahepatic microsomal enzymesExtrahepatic microsomal enzymes (oxidation, conjugation)(oxidation, conjugation)
Hepatic non-microsomal enzymesHepatic non-microsomal enzymes (acetylation, sulfation,GSH, (acetylation, sulfation,GSH, alcohol/aldehyde dehydrogenase,alcohol/aldehyde dehydrogenase,hydrolysis, ox/red)hydrolysis, ox/red)
Liver Microsomal System
•Oxidative Reactions: Cytochrome P450 mediated
• Examples– Formation of an inactive polar metabolite
• Phenobarbital
– Formation of an active metabolite• By Design: Purine & pyrimidine chemotherapy prodrugs
• Inadvertent: terfenadine – fexofenadine
– Formation of a toxic metabolite• Acetaminophen – NAPQI
Electron flow in microsomal drug oxidizing system
CO
hCYP-Fe+2
Drug
CO
O2
e-
e-
2H+
H2O
Drug
CYPR-Ase
NADPH
NADP+
OHDrug
CYP Fe+3
PCDrug
CYP Fe+2
Drug
CYP Fe+2
Drug
O2
CYP Fe+3
OHDrug
Cytochrome P450 Isoforms (CYPs) - An Overview
• NADPH + H+ + O2 + DrugNADP+ + H2O + Oxidized Drug
• Carbon monoxide binds to the reduced Fe(II) heme and absorbs at 450 nm (origin of enzyme family name)
• CYP monooxygenase enzyme family is major catalyst of drug and endogenous compound oxidations in liver, kidney, G.I. tract, skin, lungs
• Oxidative reactions require the CYP heme protein, the reductase, NADPH, phosphatidylcholine and molecular oxygen
• CYPs are in smooth endoplasmic reticulum in close association with NADPH-CYP reductase in 10/1 ratio
• The reductase serves as the electron source for the oxidative reaction cycle
CYP Families
• Twelve CYP gene families have been identified in humans, and the categories are based upon protein sequence homology
• Most of the drug metabolizing enzymes are in CYP 1, 2, & 3 families .
• CYPs have molecular weights of 45-60 kDa. • Frequently, two or more enzymes can catalyze the
same type of oxidation, indicating redundant and broad substrate specificity.
• CYP3A4 is very common to the metabolism of many drugs; its presence in the GI tract is responsible for poor oral availabilty of many drugs
CYP Nomenclature
• Families - CYP plus arabic numeral (>40% homology of amino acid sequence, eg. CYP1)
• Subfamily - 40-55% homology of amino acid sequence; eg. CYP1A
• Subfamily - additional arabic numeral when more than 1 subfamily has been identified; eg. CYP1A2
• Italics indicate gene (CYP1A2); regular font for enzyme
CYP Tables
• Human CYPs - variability and importance in drug metabolism
• Isoforms in metabolism of clinically important drugs• Factors that influence CYP activity• Drugs that inhibit CYPs• Non-Nitrogenous CYP inhibitors• Extrahepatic CYPs
Human Liver Drug CYPs CYP
enzyme Level
(%total) Extent of variability
1A2 ~ 13 ~40-fold 1B1 <1 2A6 ~4 ~30 - 100-fold 2B6 <1 ~50-fold 2C ~18 25-100-fold 2D6 Up to 2.5 >1000-fold 2E1 Up to 7 ~20-fold 2F1 2J2 3A4 Up to 28 ~20-fold 4A, 4B
2E
S. Rendic & F.J. DiCarlo, Drug Metab Rev 29:413-80, 1997
Factors Influencing Activity and Level of CYP Enzymes
S. Rendic & F. J. Di Carlo Drug Metab Rev 29: 413-580, 1997
Nutrition 1A1;1A2;2E1; 3A3; 3A4,5
Smoking 1A1;1A2
Alcohol 2E1
Drugs 1A1,1A2; 2A6; 2B6; 2C; 2D6; 3A3, 3A4,5
Environment 1A1,1A2; 2A6; 1B; 2E1; 3A3, 3A4,5
Genetic Polymorphism
1A; 2A6; 2C9,19; 2D6; 2E1
Red indicates enzymes important in drug metabolism
Participation of the CYP Enzymes in Metabolism of Some Clinically Important Drugs
S. Rendic & F.J. Di Carlo, Drug Metab Rev 29:413-580, 1997
Participation of the CYP Enzymes in Metabolism of Some Clinically Important Drugs (cont’d)
S. Rendic & F.J. Di Carlo, Drug Metab Rev 29:413-580, 1997
Drugs that Inhibit Drug Metabolism by FormingComplexes with CYPs
Amphetamine Itraconazole
Cimetidine Ketoconazole
Dapsone Methadone
2,5-Dimethoxy-4-
methylamphetamine
Methamphetamine
Nortriptyline
Diphenylhydramine SKF 525A
Erythromycin Sulfanilamide
Fenfluramine
Modified from: A. Alvares and W.B. Pratt, Pathways of Drug Metabolism in Principles of Drug Metabolism (Eds. W.B. Pratt, P.Taylor) 3rd Edition, 1990
Non-nitrogenous Substances that Effect Drug Metabolism by Forming Complexes with CYPs
• Grapefruit juice - CYP 3A4 inhibitor; highly variable effects; unknown constituents – D.G. Bailey, et al.; Br J Clin Pharmacol 1998,
46:101-110
• Isosafrole, safrole - CYP1A1, CYP1A2 inhibitor; found in root beer, perfume
• Piperonyl butoxide & alcohol -CYP1A1, CYP1A2 inducer; insecticide constituent
Overheard Conversation
• At a B&B breakfast table, after grapefruit juice was served, someone remarked “A friend read the package insert with her prescription and the fine print warned against drinking grapefruit juice…is this true? Should it be avoided with all medications? How about grapefruit itself? How about orange juice?”
Effect of Grapefruit Juice on Felodipine Plasma Concentration
5mg tablet with juice
without
Review- D.G. Bailey, et al.; Br J Clin Pharmacol 1998, 46:101-110
N
CO 2CH3CH3O2C
CH3 CH3
H
H
Cl
Cl3A4
N
CO 2CH3CH3O2C
CH3 CH3
Cl
Cl
Grapefruit Juice Facts
• GJ or G (not OJ) elevates plasma peak drug concentration, not elimination t1/2
• GJ reduced metabolite/parent drug AUC ratio• GJ caused 62% reduction in small bowel enterocyte
3A4 and 3A5 protein; liver not as markedly effected (i.v. pharmacokinetics unchanged)
• GJ effects last ~4 h, require new enzyme synthesis • Effect cumulative (up to 5x Cmax) and highly variable
among individuals depending upon 3A4 small bowel basal levels
Human Drug Metabolizing CYPs Located in Extrahepatic Tissues
S. Rendic & F.J. DiCarlo, Drug Metab Rev 29:413-80, 1997
Human Drug Metabolizing CYPs Located in Extrahepatic Tissues (cont’d)
CYP Enzyme
Tissue
2E1 Lung, placenta, others 2F1 Lung, placenta 2J2 Heart
3A GI tract, lung, placenta, fetus, uterus, kidney
4B1 Lung, placenta 4A11 Kidney
S. Rendic & F.J. DiCarlo, Drug Metab Rev 29:413-80, 1997
CYP Biotransformations
• Chemically diverse small molecules are converted, generally to more polar compounds
• Reactions include:– Aliphatic hydroxylation, aromatic hydroxylation– Dealkylation (N-,O-, S-)– N-oxidation, S-oxidation– Deamination– Dehalogenation
Examples: ibuprofen, pentobarbital
Aliphatic hydroxylation
R CH2CH3 R CHCH3
OH
ibuprofen
CO2H CO2H
HO
pentobarbital
HN
N
O
O
H
O
HN
N
O
O
H
O OH
Examples: acetanilide, phenytoin, propranololEndogenous substrates: steroid hormones (not aromatic amino acids)
Aromatic Hydroxylation R
unstable arene epoxideintermediate
non-enzymatic
HYL1epoxide
hydrolase
R OH
OH
R OH
O DNA, Proteintoxic
reactions
O
R
R
OH
R
OH
or
phenytoin
Arene epoxide intermediate produces multiple products
N
N
O
CYP2C8,9 N
N
O
OH
H
HYL1
phenytoin
3,4-dihydro-dihydroxyphentoin
N
N
O
HO
N
N
O
OH
N
N
O
HO OH
para-hydroxyphenytoin meta-hydroxyphenytoin
propranolol O
N
OH
H
ON
OH
H
OH
ON
OH
H
OH
N (or O, S)-Dealkylation R N
CH2
CH2
R
CH2
OH
R NCH2
CH2
R
CH2
R NCH2
CH2
R
CH3 R NCH2
CH2
R
CH3+
O 2
-H+-1e-
HCHO+R N
CH2
CH2
R
H
N-demethylation generates formaldehyde
ethylmorphine OO OH
NCH3
OO OH
NH
HCHO+
ethylmorphine desmethyl-ethylmorphine
N-demethylation favored over O-deakylation
propranolol O
N
OH
H
ON
OH
H
OH
ON
OH
H
OH
O
N
OH
H
H
6-methylthiopurine N
N
N
N
SCH3
N
N
N
N
SH
HCHO+
Examples: chlorpheniramine, trimethylamine
Examples: chlorpromazine, cimetidine
N-Oxidation
R NH2 R NHOH
R NR
RR N
+
RR
O_
S-Oxidation
SR
R2
SR
R2
O
chlorpromazine
chlorpheniramine N
N
Cl
N
N
Cl
O S
N Cl
N
S
N Cl
N
O
Examples: amphetamine, diazepam
R CHCH3
NH2
R C
NH2
CH3
OH R C CH3
O+ NH3
Deamination
amphetamine NH2 O
NH3+
Dehalogenation
R1R2R3 C.R1R2R3 C XRH
+ Cl-
R1R2R3 CH R.+
Example: carbon tetrachloride, others include. halothane, methoxyflurane CCl 4 CHCl 3 + R. (lipid peroxidation)
Non-CYP Drug Biotransformations• Oxidations• Hydrolyses• Conjugation (Phase 2 Rxs)
– Major Conjugation Reactions• Glucuronidation (high capacity) • Sulfation (low capacity) • Acetylation (variable capacity) • Examples:Procainamide, Isoniazid
– Other Conjugation Reactions: O-Methylation, S-Methylation, Amino Acid Conjugation (glycine, taurine, glutathione)
– Many conjugation enzymes exhibit polymorphism
Non-CYP drug oxidations
• Monoamine Oxidase (MAO), Diamine Oxidase (DAO) - MAO (mitochondrial) oxidatively deaminates endogenous substrates including neurotransmitters (dopamine, serotonin, norepinephrine, epinephrine); drugs designed to inhibit MAO used to effect balance of CNS neurotransmitters (L-DOPA); MPTP converted to toxin MPP+ through MAO-B. DAO substrates include histamine and polyamines.
• Alcohol & Aldehyde Dehydrogenase - non-specific enzymes found in soluble fraction of liver; ethanol metabolism
• Xanthine Oxidase - converts hypoxanthine to xanthine, and then to uric acid. Drug substrates include theophylline, 6-mercaptopurine. Allopurinol is substrate and inhibitor of xanthine oxidase; delays metabolism of other substrates; effective for treatment of gout.
Non-CYP drug oxidations
• Flavin Monooxygenases
– Family of enzymes that catalyze oxygenation of nitrogen, phosphorus, sulfur – particularly facile formation of N-oxides
– Different FMO isoforms have been isolated from liver, lung (D. Ziegler, 1993, Ann Rev Pharmacol Toxicol 33:179-199)
– Complete structures defined (Review: J. Cashman, 1995, Chem Res Toxicol 8:165-181)
– Require molecular oxygen, NADPH, flavin adenosine dinucleotide (FAD)
– Single point (loose) enzyme-substrate contact with reactive hydroperoxyflavin monoxoygenating agent
– FMOs are heat labile and metal-free, unlike CYPs
– Factors affecting FMOs (diet, drugs, sex) not as highly studied as CYPs
FMO Oxidations N CH3
N
H
N
N
H
CH3O
-
+
nicotine nicotine-N-oxide
FMO3 cimetidine cimeditine S-oxide
HN N
SN N
N
H H
CN HN N
SN N
N
H H
CNO
FMO3
Hydrolysis ReactionsEsters
Example: aspirin (others include procaine, clofibrate)
+ R2OHR1 OH
O
R1 OR2
O CO 2H
OCOCH 3
CO 2H
OH
Hydrolysis ReactionsAmides
Example:lidocaine; others include peptide drugs
R1 NH
R2
O
R1 OH
ONH2R2+
NH
O
NNH2N
OH
O+
Conjugation Reactions Glucuronidation
OOH
OHOOH
CO2H
P O P O
O
HO
OH
O
CH2
O NNH
O
O
OOH
OHOH
CO2HO R
+ ROH
orR3N
UGT
UDP- -D-glucuronic acidO
OH
OHOH
CO2HN+ R
R
R
O-glucuronide
N+-glucuronide
Liver has several soluble UDP-Gluc-transferases
Glucuronic acid conjugation to phenols, 3°-amines, aromatic amines
Morphine
O
HO
HO
N CH36
3
Amitriptyline
N
N
N
CH3
O
Cotinine
Conjugation Reactions Sulfation
Examples: ethanol, p-hydroxyacetanilide, 3-hydroxycoumarin
(PAPS, 3’-phosphoadenosine-5’-phosphosulfate)
R OH
R O S OH
O
O H H
NH2
N
NN
N
OH
O
H HHO
O P
OH
O
O SOH
O
O
+
Sulfation may produce active metabolite
N
N
NH2
O
H2N N
N
N
NHO
H2N N
S
O
HO
O
Minoxidil Minoxidil-sulfate
Conjugation ReactionsAcetylation
Examples: Procainamide, isoniazid, sulfanilimide, histamine
NAT enzyme is found in many tissues, including liver
Ar NH2
R SH
R OH
R NH2
+
Ar NCH3
O
H
Acetyl transferase
CoA SO
R NO
CH3H
R OO
CH3
R SO
CH3
Procainamide
Unchangedin Urine, 59%
3%24% Fast17% Slow
Unchangedin Urine, 85%
NAPA
0.3%
1%
H2N
O
N
H
N N
O
N
H
N
O
H H2N
O
N
H
N
H
NO
N
H
N
O
H H
Procainamide
trace metabolite
non-enzymatic
Lupus?
H2N
O
N
H
N N
O
N
H
NHO
H N
O
N
H
NO
Drug Conjugation Example:Isoniazid - N-acetyltransferase
• First line drug in the treatment of TB; normally given at a does of 5 mg/kg, max. 300 mg/day for period of 9 months
• Rapid and slow acetylators first seen in TB patients; t1/2 for fast is 70 min; t1/2 for slow is 180 min
• N-acetyltransferase (NAT2 isoform) is in liver, gut• Peripheral neuropathy (about 2% patients; higher
doses produce effects in 10-20%) seen in slow acetylators (reversible with pyridoxine)
• Hepatotoxicity also seen, esp. in older patients
NAT2 N
OHO
N
N N HO
H
H
N
N NO
H
H
CH3
O
minor
Isoniazid N-Acetylisoniazid
N-Acetylation may trigger nitrenium ion formation
NH2 NH
OHNH
O
C OCH3
N+
NAT2CYP1A2
Reactive Nitrenium ion
Carcinogenic DNA Adduct
Additional Effects on Drug Metabolism• Species Differences
– Major differences in different species have been recognized for many years (R.T. Williams).
• Phenylbutazone half-life is 3 h in rabbit, ~6 h in rat, guinea pig, and dog and 3 days in humans.
• Induction – Two major categories of CYP inducers
• Phenobarbital is prototype of one group - enhances metabolism of wide variety of substrates by causing proliferation of SER and CYP in liver cells.
• Polycylic aromatic hydrocarbons are second type of inducer (ex: benzo[a]pyrene).
– Induction appears to be environmental adaptive response of organism
– Orphan Nuclear Receptors (PXR, CAR) are regulators of drug metabolizing gene expression
PXR and CAR Protect Against Xenobiotics
xenobiotics
PXRPXR
RXR
CARCAR
cytoplasm nucleus
xenoprotection
target genes
S.A. Kliewer
CYP3A Inducers Activate Human, Rabbit, and Rat PXR
rifampicin
PCN
dexamethasone
RU486
clotrimazole
Reporter activity (fold)
troglitazone
1 3 5 7 9 11 13 15 17 19
tamoxifen
Cell-basedreporter assay
S.A. Kliewer
CYP3A Regulation
xenobiotics(e.g., drugs)
HO-xenobiotics
endobiotics(e.g., steroids)
HO-endobiotics
CYP3ACYP3A
CYP3A
xenobiotics
liverintestine
XRE
??
• Protect against xenobiotics• Cause drug-drug interactions
rifampicinPCN
dexamethasoneRU486
clotrimazoletroglitazonetamoxifen
• Expressed in liver and intestine• Activated by xenobiotics• Bind to Xenobiotic Response Elements
S.A. Kliewer et al.Endo Rev 23:687, 2002
Pregnane X Receptor (PXR)
human PXR LigandLigandLigandLigandDNADNADNADNA
mouse PXR 77%77%77%77%96%96%96%96%
rat PXR 76%76%76%76%96%96%96%96%
82%82%82%82%94%94%94%94%rabbit PXR
• PXR is one of Nuclear Receptor (NR) family of ligand-activated transcription factors.
• Named on basis of activation by natural and synthetic C21 steroids (pregnanes), including pregnenolone 16-carbonitrile (PCN)
• Cloned due to homology with other nuclear receptors• Highly active in liver and intestine• Binds as heterodimer with retinoic acid receptor (RXR)
S.A. Kliewer
Constitutive Androstane Receptor (CAR)
• Highly expressed in liver and intestine• Binds response elements as RXR heterodimer• High basal transcriptional activity without
ligand• Sequestered in cytoplasm• Activated by xenobiotics
– phenobarbital, TCPOBOP (1,4-bis[2-(3,5-dichloropyridyloxy)]benzene)
CAR LigandLigandDNADNA
PXR 66%66% 41%41%
CAR
PXR
CAR
PXR
S.A. Kliewer
Plasticity in the PXR Binding Pocket
hyperforinSR12813
Volume: 1280 Å3 1544 Å3
S.A. Kliewer
PXR Structure
• Large, elliptical hydrophobic cavity• The cavity changes shape to accommodate
different ligands• PXR is ideally suited to function as xeno-sensor
xenobiotics
PXRPXR RXRRXR xenobioticmetabolism
S.A. Kliewer
PXR and CAR Regulate Overlapping Genes
PCN (PXR)• Phase I enzymes
Cyp3a11Cyp2b10Aldh1a1Aldh1a7
• Phase II enzymesUgt1a1Gst-a1
• TransportersMrp2Mrp3Oatp2
(3.5x)(12x)(2.1x)(1.6x)
(2.8x)(16x)
(3.0x)(9.2x)
TCPOBOP (CAR)
(3.4x)(110x)(1.9x)(1.9x)
(15x)
(2.0x)(1.9x)
Liver RNA
S.A. Kliewer
Acetaminophen• Acetanilide – 1886 – accidentally discovered
antipyretic; excessively toxic (methemoglobinemia); para-aminophenol and derivatives were tested.
• Phenacetin introduced in 1887, and extensively used in analgesic mixtures until implicated in analgesic abuse nephropathy; 1946, Lester reported conjugated para-aminophenol as major metabolite of acetanilide
• 1948-49 Brodie and Axelrod recognized acetaminophen as the major active metabolite in phenacetin
• CAR modulates acetaminophen toxicity [Science (Oct 11) 298:422, 2002]
Acetaminophen and p-Aminophenols
Acetanilide, 1886(accidental discovery ofantipyretic activity; high toxicity)
Phenacetin or acetophenetidin, 1887 (nephrotoxic, methemoglobinemia)
Acetaminophen, 1893
Recognized as active metabolite of acetanilide and phenacetin in 1948 (Brodie &Axelrod); popular in US since 1955
70-90%75-80%
HNCOCH 3
OH
HN
COCH 3
OC 2H5
NH2
OC 2H5
HN
COCH 3 NH2
Acetominophen Metabolism
~60% ~35%
CYP2E1*CYP1A2CYP3A4
NAPQIN-acetyl-p-benzoquinone imine
*induced by ethanol, isoniazid
Protein adducts,Oxidative stressToxicity
HN
COCH 3
OH HN
COCH 3
OSO 3H
HN
COCH 3
OO CO 2H
OH
OHHO
N
O
COCH 3
•Acetaminophen overdose results in more calls to poison control centers in the United States than overdose with any other pharmacologic substance.
•The American Liver Foundation reports that 35% of cases of severe liver failure are caused by acetaminophen poisoning which may require organ transplantation.
•N-acetyl cysteine is an effective antidote, especially if administered within 10 h of ingestion [NEJM 319:1557-1562, 1988]
•Addition of N-acetyl cysteine to acetaminophen tablets proposed to prevent liver toxicity. [British Medical Journal, Vol. 323, Sept. 15, 2001]
Acetaminophen Toxicity
Acetaminophen Protein Adducts
CYP2E
HS-Protein
H2N-Protein
S.D. Nelson, Drug Metab. Rev. 27: 147-177 (1995)J.L. Holtzman, Drug Metab. Rev. 27: 277-297 (1995)
HN
COCH 3
OH
N
O
COCH 3 HN
COCH 3
OH
S Protein
HN
COCH 3
OH
NH Protein
O
COCH 3NSProtein
NAPQI toxicity linked to CAR activation,GSH depletion
N
O
COCH 3
Glutathione S-Transferase (GST Pi)
CAR
SH
glu-cys-gly
OH
S
HNCOCH3
GLU
GLYCYS
PhenobarbTCPOBOP
GST Pi
SH
glu-cys-gly
androstanol
toxicity
oxidative stressmechanism ?
Protective effect. Liver cells die (pale areas) when exposed to high doses of acetaminophen (left), but a CAR inhibitor protects against such damage (right).
Jun Zhang,* Wendong Huang,* Steven S. Chua, Ping Wei, David D. MooreScience, October 11, 298:422, 2002
Acetaminophen toxicity mechanism
• Mice nulled for glutathione S-transferase are resistant to acetaminophen toxicity
– equal amounts of acetaminophen protein adducts formed in null and wild type suggesting protein adducts may not be toxic
– hepatic GSH lowered in wild type (but not in KO) after acetaminophen
• CAR nulled mice are also resistant to acetaminophen toxicity
– hepatic GSH lowered in wild type (but not in KO) after acetaminophen
– CAR-humanized mice demonstrate same toxicity response
• N-acetyl cysteine is an effective agent to block GSH depletion and rescue from liver damaging toxicity
• NAPQI-protein adduction or NAPQI-GSH depletion-oxidative stress....to be continued
Terfenadine (Seldane©) NHO
OH
Terfenadine in the News
• DHHS/FDA: Terfenadine; Proposal to Withdraw Approval of Two New Drug Applications– Federal Register 62, January 14, 1997
• Hoechst Marion Roussel To Promote Switch From Seldane to Allegra– Independent News Service, January 14, 1997
• Citing Its Side Effects, F.D.A. Weighs Ban on Allergy Drug– The New York Times, January 14, 1997
• FDA Wants Drug Seldane Off Market– The Washington Post, January 14, 1997
• Hoechst’s First Quarter Results Below Forecasts– Independent News Service, May 7, 1997
Terfenadine• Developed in 1980s as a 2nd generation H1-antihistamine;
from introduction in 1985, prescriptions > 16 million in 1991
• First generation antihistamines are lipophilic ethylamine derivatives that readily penetrate the CNS and placenta - objective of 2nd generation is minimal CNS effects (non-sedating), not crossing the blood brain barrier; longer acting
• Cardiac side-effects are serious - inhibition of potassium channels by unmetabolized parent drug causes prolongation of QT interval leading to life threatening arrythmia (torsades de pointes); first recognized at USUHS in 1989 (Monahan BP et al, JAMA 1990; 264:2788-2790.)
• Drugs or substances inhibiting terfenadine metabolism (grapefruit juice, ketoconazole, itraconazole, antimicrobials) or liver dysfunction exacerbate the side effects
Terfenadine Metabolism
CYP3A4
Terfenadine(Seldane)
Fexofenadine(Allegra)
NHO
OH NHO
CO 2H
OH
Drug Metabolism - WWW Information Resources
•http://www.icgeb.trieste.it/p450/– Directory of P450 Containing Systems; comprehensive web
site regarding all aspects of chemical structure (sequence and 3D) of P450 proteins from all species; steroid ligands; links to related sites including leading researchers on P450
•http://www.panvera.com/tech/dmeguide/index.html– Drug Metabolism Resource Guide - catalog with useful
information and characteristics of natural and recombinant drug metabolizing enzymes; assay methods
•http://www.netsci.org/Science/Special/feature06.html– Site contains essay “The emerging role of ADME in optimizing
drug discovery and design” RJ Guttendorf, Parke-Davis
•http://www.fda.gov/cder/guidance/ – Site contains many useful documents regarding drug
metabolism and FDA recommendations including "Drug Metabolism/Drug Interaction Studies in the Drug Development Process: Studies in Vitro", FDA Guidance for Industry.