Drug Metabolism S.P. Markey Laboratory of Neurotoxicology NIMH, NIH Nov. 14, 2002.

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


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


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 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.

Drug Metabolism S.P. Markey Laboratory of Neurotoxicology NIMH, NIH Nov. 14, 2002.

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Transcript of Drug Metabolism S.P. Markey Laboratory of Neurotoxicology NIMH, NIH Nov. 14, 2002.