Drug Metabolism and DIsposition · Pharmacokinetic Interaction Between Ethanol and Ni-trendipine in...

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Drug Metabolismand DIsposition:the biological fate of chemicals

January/February 1990 Vol. 18, No. 1

CONTENTS

Pharmacokinetics and Metabolism ofthe Pharmacolog-ically Active 4’-Hydroxylated Metabolite of Pro-pranolol in the Dog. D. D. CHRIST, U. K. WALLE,

J. E. OATIS, JR., AND T. WALLE

Metabolism of Chloronitrobenzenes by Isolated RatHepatocytes. DOUGLAS E. RICKERT AND SARA D.HELD S

Effect of Microsomal Enzyme Inducers on Biliary andUrinary Excretion of Acetaminophen Metabolitesin Rats: Decreased Hepatobiliary and IncreasedHepatovascular Transport of Acetaminophen-glu-curonide after Microsomal Enzyme Induction.ZOLTAN GREGUS, CHERUKURY MADHU, AND CUR-TIS D. KLAASSEN

Comparative Studies of the In Vitro Metabolism andCovalent Binding of ‘4C-Benzene by Liver Slicesand Microsomal Fraction of Mouse, Rat, and Hu-man. JOANNE I. BRODFUEHRER AND GARTHPowis

Structural Characterization of Urinary Metabolites ofthe Antiarrhythmic Drug Encainide in HumanSubjects. HEMANT K. JA.JOO, ROBERT F. MAYOL,JOHN LABUDDE, AND IAN A. BLAIR 28

Azoreduction of Dimethylaminobenzene (DAB) in Pn-mary Cultures of Rat Hepatocytes: Effect of Hy-polipidemic Agents. ALBERT M. STODDART AND

WALTER G. LEVINE 36

Pharmacokinetics of Disopyramide in the Dog: Impor-tance of Mono-N-dealkylated Metabolite Kineticsin Assessing Pharmacokinetic Modeling of the Par-ent Drug. CHYUNG S. COOK, PETER R. GUILT, KEN

KOWALSKI, SAMIR GUPTA, JAMES OPPERMANN,AND Aziz KARIM

Purification and Characterization of Human Kidney

Cytosolic Cysteine Conjugate �3-Lyase Activity.LAWRENCE H. LASH, RITA M. NELSON, RUSSELLA. VAN DYKE, AND M. W. ANDERS 50

Pharmacokinetics of Prednisolone and Its Local Anti-

inflammatory Steroid-21-oate Ester Derivatives: InVitro and In Vivo Comparative Study. SAYED M.H. AL-HABET, IRACH B. TARAPOREWALA, ANDHENRY J. LEE

Thiol-mediated Catalysis of Nitroglycerin Degradationby Serum Proteins: Increase in Metabolism Was

Not Accompanied by S-Nitrosothiol Production.

S. CHONG AND HO-LEUNG FONG 61

Isolation and Identification of a Novel Human Metab-olite of Cyclosponn A: Dihydro-CsA M 17. G. PA-TRICK MEIER, SANG B. PARK, DENNY J. GMUR,AND GARY C. YEE 68

Phenytoin Disposition in the Pregnant Rat: Dose-de-

pendent Studies and Salicylate Effects. PATRICIACLEVELAND AND CLARENCE T. UEDA 72

A Reversible Clearance Model for the EnterohepaticCirculation of Drug and Conjugate MetabolitePair. ROBIN L. 0. SEMMES AND DANNY D. SHEN . 80

Disposition ofEthimizol, a Xanthine-related NootropicDrug, in Perfused Rat Liver and Isolated Hepato-

cytes. STEFAN BEZEK, MARIAN KUKAN, ZOLTANKALLAY, ToMA� TRNOVEC, MILAN STEFEK, ANDLEVON B. PI0TR0vSKIY

The Effect of Enzyme Induction and Inhibition on theDisposition of the Xanthine-related Nootropic

Drug Ethimizol in Perfused Liver and Hepatocyte

of Rats. MARIAN KUKAN, STEFAN BEZEK, MILANSTEFEK, ToMA� TRNOVEC, MARIA DURI�OVA, ANDLEVON PIOTROVISKIY

Placental Transfer, Tissue Distribution, and Pharma-

cokinetics of Cyclosporine in the Pregnant Rabbit.LORENZO SANGALLI, ANGELA BORTOLOTTI, FLAVIO

PASSERINI, AND MAURIzI0 BONATI 102

Metabolism of Prostaglandin F2�. in Sheep. VLADIMIR

DIM0v AND KRISTER GREEN 107

The Metabolism and Disposition of ‘4C-Fenofibrate inHuman Volunteers. ANDRE WElL, JOHN CALD-WELL, AND MARGHERITA STROLIN-BENEDETFI ... 115

Drug Interaction: Effects of Salicylate on Pharmacoki-netics of Valproic Acid in Rats. H5IU-YING Yu,YU-ZEN SHEN, YUICHI SUGIYAMA, AND MANABU

HANANO 121

SHORT COMMUNICATION

Pharmacokinetic Interaction Between Ethanol and Ni-trendipine in the Rat: Role of Hypothermia as a

Contributing Mechanism. KATHLEEN M. BOJE ANDHO-LEUNG FUNG 127

DRUG METABOLISM AND DISPOSITION (ISSN 0090-9556) is an official publication of the American Society for Pharmacology and Experimental Therapeuticsand is published bimonthly by Williams & Wilkins, 428 E. Preston St., Baltimore, MD 2 1202-3993. Second class postage paid at Baltimore, MD and at additionalmailing offices. POSTMASTER: Send address changes to DRUG METABOLISM AND DISPOSITION, 428 E. Preston St., Baltimore, MD 21202-3993. Price pervolume: USA individual rate $70; Japan $107 (includes air freight); all other countries $85 surface mail. USA institutional rate $110; Japan $147 (includes air freight);all other countries $125 surface mail. Single copy $15 ($18 foreign). Prices subject to change. Copyright © 1990 by the American Society for Pharmacology andExperimental Therapeutics.

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March/April 1990 Vol. 18, No. 2

CONTENTS

Role of P-450c in the Formation of a Reactive Inter-mediate of Chiorotrianisene (TACE) by HepaticMicrosomes from Methylcholanthrene-treated rats.

MARLENE J. JUEDES AND DAVID KUPFER 131

Metabolic Disposition Studies on Simvastatin, aCholesterol-lowering Prodrug. S. VICKERS, C. A.DUNCAN, 1-Wu CHEN, A. ROSEGAY, AND D. E.DUGGAN 138

Metabolism of Temelastine (SK&F 93944) in Hepato-

cytes from Rat, Dog, Cynomolgus Monkey, andMan. H. G. OLDHAM, P. STANDRING, S. J. NoR-MAN, T. J. BLAKE, I. BEATTIE, P. J. Cox, AND R. J.

CHENERY

Disposition in Animals of a New Anti-HIV Agent:2’,3’-Didehydro-3’-Deoxythymidine. JOHN W.RUSSELL, VALERIE J. WHITEROCK, DIANA MAR-

RERO, AND LEWIS J. KLUNK 153

Bioavailability Assessment of Cyclosporine in the Rat:Influence of Route of Administration. DAVID R.

LUKE. LANE J. BRUNNER, AND KIUMARS VADIEI . 158

Bioalkylation of Benz[a]Anthracene as a BiochemicalProbe for Carcinogenic Activity: Lack of Bioalky-

laton in a Series of Six Noncarcinogenic Polynu-clear Aromatic Hydrocarbons. JAMES W. FLESHER

AND STEVEN R. MYERS

Selective Inactivation by Chlorofluoroacetamides of theMajor Phenobarbital-inducible Form(s) of RatLiver Cytochrome P-450. JAMES HALPERT, JOHN-

YAN JAW, CELIA BALFOUR, AND LAURENCE S.

KAMINSKY

Distribution and Metabolism of the Retinoid, N-(4-

Methoxyphenyl)-all-trans-retinamide, the Major

Metabolite of N-(4-Hydroxyphenyl)-all-trans-retin-

amide, in Female Mice. THERESA A. HULTIN,MARK S. FILLA, AND DAVID L. MCCORMICK

Metabolite Inhibition of Parent Drug Biotransforma-tion: Studies of Diltiazem. S-C. TSAO, T. H. DICK-INSON, AND D. R. ABERNETHY 180

In Vivo Metabolism of Isomeric Naphthalene Oxide

Glutathione Conjugates. MICHAEL BUONARATI, A.DANIEL JONES, AND ALAN BUCKPITT 183

The Effect of the Cytochrome P-450 Suicide Inactiva-tor, l-Aminobenzotriazole, on the In Vivo Metab-

olism and Pharmacologic Activity of Flurazepam.S. CAPELLO, L. HENDERSON, F. DEGRAZIA, D.LIBERATO, W. GARLAND, AND C. TOWN 190

Determination of Hepatic Blood Flow in the Rat Using

Sequential Infusions of Indocyanine Green or Ga-lactose. GARY M. POLLACK, KIM L. R. BROUWER,KARENB.DEMBY.ANDJAMIA.JONES 197

Biotransformation of Lovastatin. I. Structure Elucida-tion ofln Vitro and In Vivo Metabolites in the Ratand Mouse. KAMLESH P. VYAS, PRASAD H. KARl,STEVEN M. PITZENBERGER, RITA A. HALPIN,HARRI G. RAMJIT, BYRON ARISON, JOAN S. MUR-

PHY, WILLIAM F. HOFFMAN, MICHAEL S.

SCHWARTZ, EDGAR H. ULM, AND DANIEL E.DUGGAN

Disposition ofa New Orally Active Dopamine Prodrug,N-(N-Acetyl-L-methionyl)O,O-bis-(ethoxycarbonyl)-dopamine (TA-870) in Humans. M. YOSHIKAWA,H. ENio, K. KOMATSU, M. FUJIHARA, 0. TAKAITI,

T. KAGOSHIMA, M. UMEHARA, AND H. ISHIKAWA

Biotransformation of Lovastatin. II. In Vitro Metabo-lism by Rat and Mouse Liver Microsomes and

Involvement ofCytochrome P-450 in Dehydrogen-ation ofLovastatin. KAMLESH P. VYAS, PRASAD H.KARl, SHIMOGA R. PRAKASH, AND DANIEL E.DUGGAN

The Effect of Aspartame on the Activity of Rat LiverXenobiotic-metabolizing Enzymes. V. A. TUTE-

LYAN, L. V. KRAVCHENKO, AND E. E. KUZMINA . . . 223

Pharmacokinetics and Biotransformation of the Cyclo-sporine Metabolite M- 17 in the Rabbit. KENNETH

COPELAND, MICHAEL LUKOWSKI, RANDALL

YATSCOFF, JAMES THLIVERIS, AND NICHOLAS

HONCHARIK

Clearance of Prednisone in Isolated Perfused Livers ofNormal and Uremic Rats: Effects of Acute and

Chronic Cyclosporine A Administration. MARTIN

EGFJORD, HENRIK DAUGAARD, AND KLAUS

OLGAARD

The Disposition of Valpromide in Rats and the IsolatedPerfused Rat Liver. HANNA BILLIG, EHUD ZIV,

HANOCH BAR-ON, AND MEIR BIALER 238

Continued on next page

DRUG METABOLISM AND DISPOSITION (ISSN 0090-9556) is an official publication of the American Society for Pharmacology and Experimental Therapeutics

and is published bimonthly by Williams & Wilkins, 428 E. Preston St., Baltimore, MD 2 1202-3993. Second class postage paid at Baltimore, MD and at additional

mailing offices. POSTMASTER: Send address changes to DRUG METABOLISM AND DISPOSITION. 428 E. Preston St.. Baltimore. MD 21202-3993. Price pervolume: USA individual rate $70: Japan $107 (includes air freight): all other countries $85 surface mail. USA institutional rate $110: Japan $147 (includes air freight):

all other countries $125 surface mail. Single copy $15 ($ 18 foreign). Prices subject to change. Copyright © 1990 by the American Society for Pharmacology andExperimental Therapeutics.

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Contents (con! ‘ci.)

Physiologically Based Pharmacokinetics of a New Pe-

nem, SUNS 555, for Evaluation of In Vivo Efficacy.AKIRA TSUJI, HITOSHI SATO, IKUMI TAMAI, HIDEKI

ADACHI, TATSURO NISHIHARA, MASAJI ISHIGURO,

NoRlo OHNUMA, AND TERUHISA NOGUCHI 245

Relative Contribution of the Gut, Liver, and Lung to

the First-Pass Hydrolysis of Orally Administered

‘4C-Fosinopril Sodium in Dogs: In Vivo and InVitro Studies. R. A. MORRISON, S. M. SINGHVI, A.

E. PETERSON, D. A. PoCrnl, AND B. H. MIGDALOF

Effect of Rat Tissue Volume on the Distribution Ki-netics of Biperiden as a Function of Age in Rats.

KOICHI YOKOGAWA, EMI NAKASHIMA, AND FUJIO

ICHIMURA 258

Enzymatic Reduction of an Epoxysuccinic Acid Deriv-ative by Rat Cecal Microflora. KIYOMI FUKUSHIMA,

MASAYUKI ARAI, ToSHlo SUWA, AND TETSUO

SATOH 264

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Drug Metabolismand Disposition:the biological fate of chemicals

May/June 1990 Vol. 18, No. 3

CONTENTS

LE1TERS TO THE EDITOR

The Role of Sulfate Conjugation in the Elimination

Kinetics of Diflunisal in the Rat. R. VERBEECK . . 267

Response to Letter to the Editor, “Diflunisal, A UniqueModel Compound for Ester and Ether Glucuroni-dation”. JIUNN H. LIN 268

COMMENTARY

The Effect of Hepatic Blood Flow on Formation ofMetabolites. K. SANDY PANG AND GERARD J.MULDER 270

Ethyl Carbamate Metabolism: In Vivo Inhibitors andIn Vitro Enzymatic Systems. TOSHINORI YAMA-

MOTO, WILLIAM M. PIERCE, JR., HARREL E. HURST,

Dl CHEN, AND WILLIAM J. WADDELL 276

Pharmacokinetics and Disposition of WR-l065 in theRhesus Monkey. D. J. MANGOLD, B. K. HUELLE,M. A. MILLER, R. S. GEARY, D. 0. T. SANCHEZ-

BARONA, N. F. SWYNNERTON, L. FLECKSTEIN, AND

T. M. LUDDEN

Inhibition of Leucine Enkephalin Metabolism in Rat

Blood, Plasma, and Tissues In Vitro by an Ami-noboronic Acid Derivative. MUNIR A. HUSSAIN,

SUSAN M. ROWE, ASHOK B. SHENVI, AND BRUCE

J. AUNGST

Nitroglycerin Metabolism in Subcellular Fractions ofRabbit Liver: Dose Dependency of Glyceryl Dini-trate Formation and Possible Involvement of Mul-tiple Isozymes of Glutathione S-Transferases.

DAVID T.-W. LAU AND LESLIE Z. BENET

Inhibition and Induction of Theophylline Metabolism

by 8-Methoxypsoralen: In Vivo Study in Rats andHumans. GLEN APSELOFF, DALE R. SHEPARD,MARK A. CHAMBERS, SOPONE NAWOOT, DENNIS

C. MAYS, AND NICHOLAS GERBER

Bromobenzene Metabolism In Vivo and In Vitro: TheMechanism of 4-Bromocatechol Formation. NA-TALIE E. MILLER, DAVID THOMAS, AND RUTH E.BILLINGS 304

Pathways of Gallopamil Metabolism: Regiochemistry

and Enantioselectivity of the O-DemethylationProcesses. ABDUL E. MUTLIB AND WENDEL L.NELSON 309

Tissue Distribution and Metabolic Disposition of Zi-dovudine in Rats. PAULO DE MIRANDA, THIMYSTA

C. BURNETrE, AND STEVEN S. GOOD 315

Isolation and Characterization of an Ether Glucuronide

of Zidovudine, a Major Metabolite in Monkeysand Humans. STEVEN S. GooD, CECILIA S. KOBLE,RONALD CROUCH, ROBERT L. JOHNSON, JANET L.RIDEOUT, AND PAULO DE MIRANDA

Effect of Growth Hormone on Caffeine Metabolism inHypophysectomized Rats. THIERRY BIENVENU,

GERARD PONS, ELISABETH REY, MARIE-ODILERICHARD, PHILIPPE D’ATHIS, MAURICE J. ARNAUD,

AND GEORGES OLIVE

Pathways of Gallopamil Metabolism: Regiochemistryand Enantioselectivity of the N-Dealkylation Proc-

esses. ABDUL E. MUTLIB AND WENDEL L.NELSON 331

Pharmacokinetics of Methysergide and Its MetaboliteMethylergometrine in the Rat. U. BREDBERG AND

L. PAALZOW 338

The Hydrolysis-Activation of the Adriamycin Cardi-oprotective Agent ICRF- 187 ((+)- 1 ,2-Bis(3,5-diox-

opiperazinyl-l-yl)propane). BRIAN HASINOFF . . . . 344

Oxidative Cleavage of the Pentyl Side-Chain of Can-nabinoids: Identification of New Biotransforma-

tion Pathways in the Metabolism of 4’-Hydroxy-�\9-Tetrahydrocannabinol in the Mouse. D. J.HARVEY

Tolbutamide Hydroxylation by Human, Rabbit, andRat Liver Microsomes and By Purified Forms ofCytochrome P-450. MAURICE E. VERONESE, MI-CHAEL E. MCMANUS, PISAMAI LAUPATTARAKASEM,

JOHN 0. MINERS, AND DONALD J. BIRKETr

Mexiletine Metabolism In Vitro by Human Liver. F.BROLY, C. LIBERSA, AND M. LHERMITTE 362

Glucuronidation of 3’-Azido-3’-Deoxythymidine byRat and Human Microsomes. ERIKA M. CRETFON,D. VINCENT WATERHOUS, RAE BEVAN, AND JEAN-PIERRE SOMMADOSSI 369

Metabolism of Alachlor by Rat and Mouse Liver andNasal Turbinate Tissues. PAUL C. C. FENG, ALANG. WILSON, ROBERT H. MCCLANAHAN, JAMES E.

PATANELLA, AND STEPHEN J. WRATTEN 373

c�ontinued on next page

DRUG METABOLISM AND DISPOSITION (ISSN 0090-9556) is an official publication of the American Society for Pharmacology and Experimental Therapeuticsand is published bimonthly by Williams & Wilkins, 428 E. Preston St., Baltimore, MD 2 1202-3993. Second class postage paid at Baltimore, MD and at additional

mailing offices. POSTMASTER: Send address changes to DRUG METABOLISM AND DISPOSITION, 428 E. Preston St., Baltimore, MD 21202-3993. Price pervolume: USA individual rate $70; Japan $107 (includes air freight): all other countries $85 surface mail. USA institutional rate $1 10; Japan $147 (includes air freight);

all other countries $125 surface mail. Single copy $15 ($18 foreign). Prices subject to change. Copyright © 1990 by the American Society for Pharmacology and

Experimental Therapeutics.

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The Effect of Primary Metabolites of the Xanthine-Related Nootropic Drug Ethimizol on Its HepaticExtraction Ratio. MARIAN KUKAN, STEFAN BEZEK,

TOMAS TRNOVEC, AND LEVON B. PIOTROVSKIY... 378

SHORT COMMUNICATION

cDNA-Directed Expression of Rat P450s IIA1 andIIA2: Catalytic Activities Toward Steroids and

Xenobiotics and Comparison with the EnzymesPurified from Liver. TOSHIFUMI AOYAMA, KEN-

NETH KORZEKWA, TAMIHIDE MATSUNAGA, Ki-YOSHI NAGATA, JAMES GILLETTE, HARRY Y. GEL-

BOIN, AND FRANK J. GONZALEZ 383

Erratum 386

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July/August 1990 Vol. 18, No. 4

CONTENTS

Letter to the Editor and Response 387

Interspecies Differences in Stereoselective Protein Bind-ing and Clearance of MK-57 1 . D. J. T0CC0, F. A.DELUNA, A. E. W. DUNCAN, J. H. HSIEH, AND J.H.LIN 388

Comparison of the Interactions of Pyrazole and itsMetabolite 4-Hydroxypyrazole with Rat Liver Mi-crosomes. LIVIU A. CLEJAN AND ARTHUR I.

CEDERBAUM 393

Tissue, Species, and Substrate Concentration Differ-ences in the Position-selective Hydroxylation of N-Nitrosodibutylamine: Relationship to the Distri-bution of Cytochrome P-450 Isozymes 2 (IIB) andS (IVB). JOHANNES SCHULZE, ELMAR RICHTER,AND RICHARD M. PHILPOT

Effects of Thyroid Dysfunction on Prednisolone andPrednisone Interconversion and Disposition in theRat. RYO MURATA, DAVID B. HAUGHEY, AND WIL-LIAM J. JUSKO 403

Metabolic Fate ofAlclometasone Dipropionate in Rats,Rabbits, and Mice: Metabolic Products and Path-way Following Subcutaneous Administration. S.AOYAMA AND K. KAMATA 409

The Role ofCytochromes P-450 and Flavin-containingMonooxygenase in the Metabolism of(S)-Nicotineby Rabbit Lung. DAVID E. WILLIAMS, MARK K.SHIGENAGA, AND NEAL CASTAGNOLI, JR 418

A Pharmacokinetic Model for Isosorbidedinitrate, Iso-sorbide-2-mononitrate, and Isosorbide-S-mononi-trate. D. SMITH, W. ALDRICH, M. DEY, R. ENEVER,

R. WARNER, AND R. WEIERSTALL 429

Interspecies Comparison of the Pharmacokinetics ofAldose Reductase Inhibitors. R. K. BRAZZELL, Y.H. PARK, C. B. WOOLDRIDGE, B. MCCUE, R. BAR-

KER, R. COUCH, AND B. YORK 435

Metabolism and Disposition of Clarithromycin in Man.J. L. FERRERO, B. A. Bopp, K. C. MARSH, S. C.QUIGLEY, M. J. JOHNSON, D. J. ANDERSON, J. E.LAMM, K. G. TOLMAN, S. W. SANDERS, J. H.CAVANAUGH, AND R. C. SONDERS

Deuterium Isotope Effect on the Toxicokinetics ofMonomethylamine in the Rat. ANTHONY J. STREE-TER, RAYMOND W. NIM5, PAMELA R. SHEFFELS,

JOSEPH A. HRABIE, LENA OHANNESIAN, YOUNG-

HUN HEUR, BRUCE A. MIC0, AND LARRY K.KEEFER 447

N-Depyridination and N-DedimethylaminoethylationofTripelennamine and Pyrilamine in the Rat: NewMetabolic Pathways. S. Y. YEH 453

Stimulation Mechanism of Guinea Pig Liver-mediatedReduction of Naloxone by Morphine. YoSHrro

KUMAGAI, TAKASHI TODAKA, SHIGERU YAMANO,

AND SATOSHI T0KI 462

Effect of Recombinant Human Interleukin-1f3 and Tu-

mor Necrosis Factor a on Liver Cytochrome P-450 and Serum a-l-Acid Glycoprotein Concentra-tions in the Rat. CHRISTIAN PoUs, JEAN-PAUL GI-ROUD, CHANTAL DAMAIS, DENIS RAICHVARG, ANDLAURENCE CHAUVELOT-MOACHON

The Pharmacokinetics of Etodolac Enantiomers in theRat: Lack of Pharmacokinetic Interaction BetweenEnantiomers. DI0N R. BROCKS AND FAKHREDDIN

JAMALI 471

In Vitro and In Vivo Biotransformation of Simvastatin,an Inhibitor of HMG CoA Reductase. S. VICKERS,C. A. DUNCAN, K. P. VYAS, H. P. KARl, B. ARISON,

S. R. PRAKASH, H. G. RAMJIT, S. M. PITZENBER-

GER, G. STOKKER, AND D. E. DUGGAN

Species-dependent Enantioselective Plasma ProteinBinding of MK-57 1, a Potent Leukotriene D4 An-tagonist. JIUNN H. LIN, FLORENCIA A. DELUNA,EDGAR H. ULM, AND DOMINICK J. TOCCO 484

Structural Determination of the Conjugated Metabo-lites of Ritodrine. WAYNE T. BRASHEAR, BETTY R.KUHNERT, AND ROBERT WEI 488

Effects of Age and Dose on Disposition and Metabolismof Salicylic Acid in Male Fischer 344 Rats. TIMO-

THY F. MCMAHON, JANET J. DILIBERTO, ANDLINDA S. BIRNBAUM 494

Inhibition of the Metabolism of Ethyl Carbamate byAcetaldehyde. NORIMITSU KURATA, RAY KEMPER,HARRELL E. HURST, AND WILLIAM J. WADDELL . 504

Radioimmunoassay of Nicotine-i’ ‘#{176}�-Iminium Ion, anIntermediate Formed During the Metabolism of

Nicotine to Cotinine. R. SCOTT OBACH AND HELENVAN VUNAKIS 508


DRUG METABOLISM AND DISPOSITION (ISSN 0090-9556) is an official publication of the American Society for Pharmacology and Experimental Therapeuticsand is published bimonthly by Williams & Wilkins, 428 E. Preston St., Baltimore, MD 2 1202-3993. Second class postage paid at Baltimore, MD and at additional

mailing offices. POSTMASTER: Send address changes to DRUG METABOLISM AND DISPOSITION, 428 E. Preston St., Baltimore, MD 21202-3993. Price pervolume: USA individual rate $70; Japan $107 (includes air freight); all other countries $85 surface mail. USA institutional rate $110; Japan $147 (includes air freight);all other countries $125 surface mail. Single copy $15 ($18 foreign). Prices subject to change. Copyright © 1990 by the American Society for Pharmacology andExperimental Therapeutics.

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Contents (cont’d)

Biotransformation of Halothane in Guinea Pig LiverSlices. H. N. GHANTOUS, J. FERNANDO, A. J. GON-

DOLFI, AND K. BRENDEL 514

Effects of Vanadate on Hepatic Cytochrome P-450Expression in Streptozotocin-diabetic Rats. B. S.DONAHUE AND E. T. MORGAN 519

Studies on the Metabolism and Chiral Inversion ofIbuprofen in Isolated Rat Hepatocytes. SUSAN M.SANIN5, WADE J. ADAMS, DAVID G. KAISER, GOR-DON W. HALSTEAD, AND THOMAS A. BAILLIE.... 527

Morphologic Changes and Covalent Binding of 1,1-Dichloorethylene in Clara and Alveolar Type IICells Isolated from Lungs of Mice Following InVivo Administration. P. G. FORKERT, B. A.

GEDDES, D. W. BIRCH, AND T. E. MASSEY

SHORT COMMUNICATIONS

Unsubstituted Amides: New Class of Potent Inhibitorsof Human Microsomal Epoxide Hydrolase. BRAD-

LEY M. KERR AND REN#{201}H. LEVY 540

Effects of Carbon Tetrachlorde Administration toGuinea Pigs on Cytochromes P-450 and Antioxi-

dant Levels in the Inner and Outer Zones of theAdrenal Cortex. D. A. STAATS, D. P. LOHR, AND

H. D. COLBY

Isolation and Characterization of an Unusual Glucu-ronide Conjugate of Rimantadine. S. Y. BROWN,W. A. GARLAND, AND E. K. FUKUDA 546

Microsomal Metabolism of the 1“,l”-DimethylheptylAnalogue of Cannabidiol: Relative Percent of Mo-nohydroxy Metabolites in Four Species. E. SA-MARA, N. K. BROWN, AND D. J. HARVEY 548

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Drug Metabolismand DisposItion:the biological fate of chemicals

September/October 1990 Vol. 18, No. 5

CONTENTS

Letter to the Editor: Expressing the Specificity and thePotency of Cytochrome P-450 Inducers Toward7-Ethoxyresorufin. MORENO PAOLINI, GI0RGI0

CANTELLI FORTI, AND CARLO BAUER

Response S. J. GLASS AND R. B. L. VAN LIER

Bioavailability, Metabolism, and Renal Excretion ofBenzoic Acid in the Channel Catfish (Icialurus

Punctatus). STEVEN M. PLAKAS AND MARGARET

0. JAMES 552

Isozymes of Cytochrome P-450 that Metabolize Naph-thalene in Liver and Lung of Untreated Mice.KIY0SHI NAGATA, BRIAN M. MARTIN, JAMES R.

GILLETTE, AND HENRY A. SASAME 557

Effect of Diabetes on Disposition and Renal Handling

of Cefa.zolin in Rats. MASAYUKI NADAI, HIDEO

YOSHIZUMI, TAKAFUMI KUZUYA, TAKAAKI HASE-

GAWA, IKUO JOHNO, AND SHIKIFUMI KITAZAWA . 565

Identification of Urinary Metabolites of Cannabidiolin the Dog. E. SAMARA, M. BIALER, AND D. H.HARVEY 571

First-Pass Metabolism of Gentisamide: Influence ofIntestinal Metabolism on Hepatic Formation of

Conjugates. Studies in the Once-Through Vascu-larly Perfused Rat Intestine-Liver Preparation.HIROKI HIRAYAMA AND K. SANDY PANG

Estimations of Intestinal and Liver First-Pass Metabo-lism In Vivo: Studies on Gentisamide Conjugationin the Rat. HIR0KI HIRAYAMA, JOHN MORGADO,

IZABELLA GASINSKA, AND K. SANDY PANG 588

Cyclosporin A Drug Interactions: Screening for Induc-ers and Inhibitors of Cytochrome P-450 (Cyclo-sporin A Oxidase) in Primary Cultures of HumanHepatocytes and in Liver Microsomes. LYDIANE

PICHARD, ISABELLE FABRE, GERARD FABRE,

JACQUES DOMERGUE, BERNARD SAINT AUBERT,

GEORGES MOURAD, AND PATRICK MAUREL

In Vitro Metabolism of the Novel Anti-inflamma-

tory Agent 6-(4’-Fluorophenyl)-S-(4’-pyridyl)-2,-dihydroimidazo-�2,lb�-thiazole. M. 0. HOW-

ARD, J. F. NEWTON, D. J. KEOHANE, L. P. Y0DIS,

C. M. SAVERINO, C. W. QUALLS, JR., AND L. W.SCHWARTZ

The Disposition of 2-Cyano-l-methyl 3-(4-(4-methyl-6-oxo- 1,4,S,6-tetrahydro-pyridazin-3-yl)phenyl)-

guanidine in Animals. DAVID G. WALKER, MI-

CHAEL HUTCHISON, TERESA A. SHEPARD, PETER M.OSBORNE, SUSAN M. ALLENBY, ANDREW J. WEBB,NICHOLAS J. VINEY, MARTIN A. PUE, RICHARD J.

CHENERY, PHILLIPA J. WooD, AND DEREK A.ROSS

Absorption of a Novel Prodrug of L-DOPA, I.-3-(3-

Hydroxy-4-pivaloyloxyphenyl)alanine (NB-355):In Vitro and In Situ Studies. AKIEIIRO HISAKA,

SATOE KASAMATSU, NORIHIR0 TAKENAGA, AND

MASAKATSU OHTAWA

The Formation, Disposition, and Hepatic Metabolism

of Dimethylnitrosamine in the Pig. G. W. HAR-

RINGTON, P. N. MAGEE, H. M. PYLYPIW, JR., R.KOZENIAUSKAS, R. F. BEVILL, D. R. NELSON, ANI)

J. C. TI-IURMON

Thiopurine Methyltransferase Isozymes in HumanRenal Tissue. JON A. VAN LOON AND RICHARD M.WEINSHILBOUM 632

Covalent Binding of Zomepirac Glucuronide to Pro-teins: Evidence for a Schiff Base Mechanism.PHILIP C. SMITH, LESLIE Z. BENET, AND ANTONY

F. MCDONAGH 639

Identification and Distribution in the Rat of AcidicMetabolites ofTamoxifen. PETER C. RUENITZ AND

NITIN T. NANAVATI 645

Pretranslational Suppression of Cytochrome P-450h(IIC 1 1) Gene Expression in Rat Liver after Admin-istration of Interferon Inducers. EDWARD T. MOR-GAN AND CATHERINE A. NORMAN 649

Pharmacokinetics of the Anti-AIDS Drug 2’,3’-Di-deoxyinosine (NSC 612049) in the Rat. GENE

F. RAY, WILLIAM D. MASON, ANI) MOSTAFA Z.BADR 654

Metabolism and Cytotoxicity of Acetaminophen in He-patocyte Cultures From Rat, Rabbit, Dog, andMonkey. TERESA A. SMOLAREK, CATHERINE V.HIGGINS, AND DAVID E. AMACHER 659

Metabolism of the Carcinogen 3-Methylcholanthrenein Human Bone Marrow Preparations. STEVEN R.MYERS AND JAMES W. FLESHER 664

Pharmacokinetics of Codeine After Parenteral and OralDosing in the Rat. JAYMIN SHAH AND WILI.IAM D.MASON


and is published bimonthly by Williams & Wilkins, 428 E. Preston St.. Baltimore. MD 21202-3993. Second class postage paid at Baltimore. MD and at additionalmailing offices. POSTMASTER: Send address changes to DRUG METABOLISM AND DISPOSITION, 428 E. Preston St.. Baltimore. MD 21202-3993. Price pervolume: USA individual rate $70: Japan $107 (includes air freight): all other countries $85 surface mail. USA institutional rate $1 10: Japan $147 (includes air freight):

all other countries $all other countries $125 surface mail. Single copy $15 ($ 18 foreign). Prices subject to change. Copyright (© 1990 by the American Society for

Pharmacology and Experimental Therapeutics.

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Contents (cont ‘d)

Excretion and Metabolism of Recainam, a New Anti-arrhythmic Drug, in Laboratory Animals and Hu- 819

Pharmacokinetics of a Novel Butylated Hydroxy-toluene-Thiazolidinone CNS Antiischemic AgentLY256548 in Rats, Mice, Dogs, and Monkeys.K. J. Ruterbories and T. D. Lindstrom 674

Acetylator Genotype-dependent Expression of Arylam-me N-Acetyltransferase and N-HydroxyarylamineO-Acetyltransferase in Syrian Inbred HamsterIntestine and Colon: Identity with the HepaticAcetylation Polymorphism. FREDRICK OGOLLA,

RONALD J. FERGUSON, WARD G. KIRLIN, ALMA

TRINIDAD, ALLEN F. ANDREWS, MANDI MPEZO,

AND DAVID W. HEIN

Stereochemical Differences in the Metabolism of 3,4-Methylenedioxymethamphetamine In Vito and InVitro: A Pharmacokinetic Analysis. ARTHUR K.

CHO, MASAYUKI HIRAMATSU, EMMA W. DIsTE-

FANO, ANN S. CHANG, AND DONALD J. JENDEN..

Glucuronidation of 2-Arylpropionic Acids Pirprofen,Flurbiprofen, and Ibuprofen by Liver Microsomes.J. MAGDALOU, V. CHAGES, C. LAFAURIE, AND G.SIEST 692

Identification of DP- 1904 and its Ester Glucuronide inHuman Urine and Determination ofTheir Enan-

tiomeric Compositions by High Performance Liq-uid Chromatography with Optical Activity andUltraviolet Detection. MAKOTO TANAKA, KENJI

ON0, HIDEO HAKUSUI, TosHlo TAKEGOSHI. Y0SH-IFUMI WATANABE, AND MUNEFUMI KANAO

Biotransformation of Sufentanil in Liver MicrosomesofRats, Dogs, and Humans. K. LAVRIJSEN, J. VAN

HOUDT, D. VAN DYCK, J. HENDRICKX, W. LAU-

WERS, R. HURKMANS, M. BOCKX, C. JANSSEN, W.

MEULDERMANS, AND J. HEYKANTS

Identification of the Rabbit and Human CytochromesP-45OIIIA as the Major Enzymes Involved in theN-Demethylation of Diltiazem. LYDIANE PICHARD,

GERARD GILLET, ISABELLE FABRE, ISABELLEDALET-BELUCHE, CLA U DE BONFILS, JEAN-PAUL

THENOT, AND PATRICK MAUREL

Metabolism of Benzene in Rat Hepatocytes: Influenceof Inducers on Phenol Glucuronidation. D.SCHRENK AND K. W. BOCK 720

Distribution and Disposition ofTrospectomycin Sulfatein the In Vito Rat, Perfused Rat Liver, and Cul-tured Rat Hepatocytes. JEFFREY W. Cox, L. GRA-HAM DRING, LEONARD C. GINSBERG, PHILIP G.LARSON, DEBORAH A. CONSTABLE, AND ROGER G.ULRICH

Influence of a Single Dose of Ethanol on the Kineticsof Valproic Acid in Rats. I. G. ALONSO, J. M.LANAO, M. I. MARTIN, A. MATEOS, A. D0MIN-

GUEZ-GIL HURLE, AND J. FERMOSO 732

The Identification of Urinary Metabolites of Doxepinin Patients. YUE-ZHONG SHU, JOHN W. HUBBARD,

JOHN K. COOPER, GORDON MCKAY, ELARIEN D.KORCHINSKI, RAKESH KUMAR, AND KAMAL K.MIDHA

Induction of Cytochrome P-450 Isozyme 3a (P-450I1E 1) in Rabbit Olfactory Mucosa by Ethanoland Acetone. XINXIN DING AND MINOR J. COON. 742

mans. J. A. SCATINA, D. S. WELLS, H. B. KIMMEL,

C. J. KEMPER, AND S. F. SISENWINE 746

Metabolism of 2-Chloro-1, 1-difluoroethane to Glyox-ylic and Glycolic Acid in Rat Hepatic Microsomes.MAX T. BAKER, MARIA T. VASQUEZ, JAMES N.BATES, AND CHAO-KUO CHIANG 753

Interaction of Continine with Rat Hepatic MicrosomalP-450: Comparison with Metyrapone and Immu-nomodulation ofContinine and Metyrapone Bind-ing by Monoclonal Anti-continine Antibodies.ROBERT J. BJERCKE, DIANNE K. HAMMOND,

HENRY W. STROBEL, AND JOHN J. LANGONE . ...

Hepatic Protein Arylation, Glutathione Depletion, andMetabolite Profiles of Acetaminophen and a Non-hepatotoxic Regioisomer. 3 ‘ -Hydroxyacetanelide,in the Mouse. MOHAMED S. RASHED, TIMOTHY G.MYERS, AND SIDNEY D. NELSON

Metabolism of 1 , l-Dichloro-cis-diphenylcyclopropaneby Rat Liver Microsomes. 0. CAPUTO, G. GROSA,

M. CERUTI, F. ROCCO, AND G. BIGLINO 771

Identification of the Urinary Metabolites of Tacrine inthe Rat. ROBERT S. HSU, GREGORY M. SHUTSKE,

EVA M. DILEO, SUSAN M. CHESSON, ANASTASIA R.

LINVILLE, AND RICHARD C. ALLEN 779

Hepatic Microsomal Metabolism of Sulfamethoxazoleto the Hydroxylamine. ALASTAIR E. CRIBB AND

STEPHEN P. SPIELBERG 784

Factors Affecting the Expression of TrifluoroacetylatedLiver Microsomal Protein Neoantigens in RatsTreated with Halothane. J. GERALD KENNA,

JACKIE L. MARTIN, HIROK0 SATOH, AND LANCE

R. POHL

The Metabolic Fate of Stiripentol in the Rat: Studieson Cytochrome P-450-mediated MethylenedioxyRing Cleavage and Side-chain Isomerism. KANYIN

ZHANG, FRANCIS LEPAGE, GERARD CUVIER,

JACQUES ASTOIN, MOHAMED S. RASHED, AND

THOMAS A. BAILLIE

The Metabolic Pathways of Tianeptine, a New Anti-depressant, in Healthy Volunteers. LUC GRISLAIN,

PATRICK GELE, MARC BERTRAND, WIM LUIJTEN,

NORBERT BROMET, CATHERINE SALVADORI, AND

ANNIE KAMOUN


Pharmacokinetics and Protein Binding of SalicylateMetabolites in Rats. MARILYN E. MORRIS 809

Age-associated Alterations in Diazepam-metabolizingEnzyme Activities in Male and Female Rats. SH0-ICHI FUJITA, JUN TATSUNO, KENICHI KITANI,

AND TOKUJI SUZUKI 812

Disposition and Metabolism of OligodeoxynucleosideMethylphosphonate Following a Single iv Injectionin Mice. TIAN-LING CHEN, PAUL S. MILLER, PAUL

0. P. Ts’o, AND 0. MICHAEL COLVIN 815

Influence of Isoniazid, Phenobarbital, Phenytoin, Preg-nenolone 16ct-Carbonitrile, and f3-Naphthoflavoneon Halothane Metabolism and Hepatotoxicity.MARK A. JENNER, JOHN L. PLUMMER, AND MI-

CHAEL J. COUSINS

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and is published bimonthly by Williams & Wilkins. 428 E. Preston St., Baltimore, MD 2 1202-3993. Second class postage paid at Baltimore. MD and at additionalmailing offices. POSTMASTER: Send address changes to DRUG METABOLISM AND DISPOSITION. 428 E. Preston St.. Baltimore. MD 21202-3993. Price pervolume: USA individual rate $75: all other countries $95 surface mail. USA institutional rate $120: all other countries $140 surface mail. Single copy $15 ($18 foreign).

Prices subject to change. Copyright © 1990 by the American Society for Pharmacology and Experimental Therapeutics.

Drug Metabolismand Disposition:the biological fate of chemicals

November/December 1990 Vol. 18, No. 6

CONTENTSBest Paper Award for 1989 823

The 1988 Bernard B. Brodie Award Lecture: FunctionalDiversity of Hepatic Cytochromes P-450. WAYNE

LEVIN 824

Pharmacokinetics and Tissue Distribution ofthe ReninInhibitor N-(2-CR)-Benzyl-3-tert-butyl-sulfonyl-propionyl�his�chacval�N�butylamine in Marmo-sets. F. CUMIN, C. SCHNELL, P. RICHERT, F. RASCH-DORF, A. PROBST, K. SCHMID, J. M. WOOD, AND

M. DE GASPARO

Dose-Dependent Pharmacokinetics of MK-4 17, a Po-tent Carbonic Anhydrase Inhibitor, in Rabbits Fol-lowing Single and Multiple Doses. JIUNN H. LIN,

1-WU CHEN, EDGAR H. ULM, JOHN R. GEHRET,AND DANIEL E. DUGGAN

Disposition and Metabolism ofCarbovir in Mice DosedIntravenously or Orally. S. M. EL DAREER, K. F.TILLERY, L. M. ROSE, R. F. STRUCK, AND D. L.HILL 842

Disposition of Amiodarone and its Proximate Metab-olite, Desethylamiodarone, in the Dog for OralAdministration of Single-Dose and Short-TermDrug Regimens. JAMES F. BRIEN, SANDRA JIMMO,

F. JAMES BRENNAN, PAUL W. ARMSTRONG, ANDHOSHIAR ABDOLLAH

Pharmacokinetics, N-Glucuronidation, and N4-Acety-lation of Sulfa-6-Monomethoxine in Humans.TOM B. VREE, ELEONORA W. J. BENEKEN KOLMER,

YECHIEL A. HEKSTER, MINORU SHIMODA, MAKOTOONO. AND IADAYOSHI MIURA

Progesterone Metabolism in Hepatic Microsomes: Ef-fect of the Cytochrome P-450 Inhibitor, Ketocon-azole, and the NADPH 5a-Reductase Inhibitor, 4-MA, upon the Metabolic Profile in Human, Mon-key, Dog, and Rat. DAVID C. SWINNEY

Metabolism of Citral, an a, $-Unsaturated Aldehyde,in Male F344 Rats. J. J. DILIBERTO, P. SRINIVAS,

D. OVERSTREET, G. USHA, L. T. BURKA, AND L. S.BIRNBAUM 866

Metabolism of Diphenyl Sulfoxide in Perfused GuineaPig Liver: Involvement of Aldehyde Oxidase as aSulfoxide Reductase. SHIN’ICHI YOSHIHARA AND

KIYOSHI TATSUMI 876

Life Span Profiles of Glutathione and AcetaminophenDetoxification. THERESA S. CHEN, JOHN P. RICHIE,

JR., AND CALVIN A. LANG 882

Metabolism of the Anticonvulsant Agent Zonisamidein the Rat. DWIGHT D. STIFF AND MICHAEL A.

ZEMAITIS 888

Taxol Metabolism: Isolation and Identification of ThreeMajor Metabolites of Taxol in Rat Bile. BERNARDMONSARRAT, ERIC MARIEL, SUZIE CROS, MICHELE

GARES, DANIEL GUENARD, FRANcOISE GUERITTE-VOEGELEIN, AND MICHEL WRIGHT

Physiological Pharmacokinetics of a New Muscle-Re-laxant, Inaperisone, Combined with its Pharma-

cological Effect on Blood Flow Rate. OSAMU NA-

GATA, MITSUO MURATA, HIDEO KATO, TETSUYA

TERASAKI, HIT05HI SATO, AND AKIRA TSUJI

Metabolism ofHexafluoropropene: Evidence for Bioac-tivation by Glutathione Conjugate Formation inthe Kidney. MICHAEL KOOB AND WOLFGANG

DEKANT 911

In Vivo Metabolites of S-(2-Benzothiazolyl)-L-Cysteineas Markers of In VIv() Cysteine Conjugate f3-Lyaseand Thiol Glucuronosyl Transferase Activities.ADNAN A. ELFARRA AND IN YOUNG HWANG . . . 917

Metabolism and Disposition of the Dopamine Agonist2-(N-Propyl-N-2-Thienylethylamino)-5-Hydroxy-tetralin in Conscious Monkeys after SubsequentIntravenous, Oral, and Ocular Administration. T.K. GERDING, B. F. H. DRENTLI, R. A. DE ZEEUW.P. G. TEPPER, AND A. S. HORN

Metabolism and Covalent Binding of [‘4CjToluene byHuman and Rat Liver Microsomal Fractions andLiver Slices. DENNIS E. CHAPMAN, TRACY J.MOORE, SANDRA R. MICIIENER, ANI)GARTIIP0WIS

Diflunisal Disposition: Role of Gastric Absorption inthe Development of Mucosal Damage and Anti-Inflammatory Potency in Rodents. BERND NUERN-

BERG, ISTVAN SZELENYI, H. THOMAS SCHNEIDER,AND KAY BRUNE

Cytochrome P-450 Isozymes Involved in MetabolicActivation of �s9-Tetrahydrocannabinol by RatLiver Microsomes. SHIZUO NARIMATSU, KAZUHITOWATANABE, TAMIHIDE MATSUNAGA, IKU0 YAMA-

MOTO, SUSUMU IMAOKA, YOSHIHIKO FUNAE, AND

HIDETOSHI YOSHIMURA

The Metabolism of Etintidine in Rat, Dog, and Human.F. A. WONG, J. R. LLOYD, AND D. W. GRADEN.. 949

Ciprofloxacin Does Not Impair the Elimination of Di-


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(‘ontents (cont ‘d.)

Subject Index 1111

azepam in Humans. W. J. A. WIJNANDS, J. F. G.TROOSTER, P. C. TEUNISSEN, H. A. CATS, AND T.B. VREE 954

Identification of N-Acetyl-S-(2,5-dihydroxyphenyl)-L-

Cysteine as a Urinary Metabolite of Benzene,Phenol, and Hydroquinone. DONALD E. NERLANDAND WILLIAM M. PIERCE, JR 958

Effects of Sodium Salicylate on Elimination Kinetics ofIndomethacin and Bile Production in Dogs. W. S.BECK, K. DIETZEL, G. GEISSLINGER, H. ENGLER,H. VERGIN, AND K. BRUNE 962

Disposition in Humans of Racemic Picenadol, an

Opioid Analgesic. PAULA M. FRANZ, SALLY L.ANLIKER, JOHN T. CALLAGHAN, KARL A. DE-SANTE, PATRICIA H. DHAHIR, ROBERT L. NELSON,

AND ALAN RUBIN

Isotope Effect Studies on the Mechanism of the Cyto-

chrome P-450I1A 1-Catalyzed Formation of �

Testosterone from Testosterone. KENNETH R.KORZEKWA, WILLIAM F. TRAGER, KIY0sHINAGATA, ANDREW PARKINSON, AND JAMES R.GILLETTE

Metabolic Disposition of Trimetrexate, a NonclassicalDihydrofolate Reductase Inhibitor, in Rat andDog. BRADLEY K. WONG, THOMAS F. WOOLF,TSUN CHANG, AND LLOYD R. WHITFIELD 980

Pharmacokinetics ofPropafenone Enantiomers in Rats.REZA MEHVAR 987

Oxidative Defluorination of 1 , 1, l,2-Tetrafluoroethane

by Rat Liver Microsomes. MICHAEL J. OisoN,CHARLES A. REIDY, JOHN T. JOHNSON, ANDTHOMAS C. PEDERSON 992

The Use of Pig Hepatocytes to Study the Biotransfor-mation offl-Nortestosterone by Pigs: Identificationof Glucuronidated 15a-Hydroxy-norandrostene-dione as an Important In Vitro and In Vivo Metab-olite. L. A. P. HOOGENBOOM, M. C. J. BERGHMANS,A. VAN VELDHUIZEN, AND H. A. KUIPER

Quinolone Inhibition ofCytochrome P-450-DependentCaffeine Metabolism in Human Liver Micro-

somes. U. FUHR, T. WOLFF, S. HARDER, P. SCHY-

MANSKI, AND A. H. STAIB 1005

Pulmonary Elimination and Metabolism of 5-Fluoro-2’-Deoxyuridine in Isolated Perfused Rat Lung andLung Slices. H. FOTH, J. HELLKAMP, E.-M. KU-NELLIS,ANDG.F.KAHL 1011

Plasma Elimination and Urinary Excretion of Metha-

pyrilene in the Rat. DANIEL W. KELLY, CLAUDE

L. HOLDER, WALTER A. KORFMACHER, AND WIL-

LIAM SLIKKER, JR 1018

Metabolism of Antiparkinson Agent Dopazinol by RatLiver Microsomes. KAMLESH P. VYAS, PRASAD H.K�RI, HARRI G. RAMJIT, STEVEN M. PITZENBER-GER, AND MARTIN HICHENS 1025

Three N-Aralkylated Derivatives of l-Aminobenzotria-

zole as Potent and Isozyme-Selective, Mechanism-Based Inhibitors of Guinea Pig Pulmonary Cyto-chrome P-450 In Vitro. KIMBERLY J. WOODCROFT,

EDWARD W. SZCZEPAN, LEAH C. KNICKLE, AND

JOHN R. BEND 1031

Formation and Reversibility ofS-Linked Conjugates ofN-(1-Methyl-3,3-diphenylpropyl)isocyanate, an InVitro Metabolite of N-(l-Methyl-3,3-diphenylpro-

pyl)formamide, in Rats. ABDUL E. MUTLIB, RASMYE. TALAAT, J. GREG SLATTER, AND FRANK S.ABBOTT 1038

In Vitro Metabolism of(-)-Cis-3-[2-Hydroxy-4-(1, 1-di-methylheptyl)phenyl]-trans-4-(3-hydroxypropyl)Cyclohexanol, a Synthetic Bicyclic CannabinoidAnalog. BRIAN F. THOMAS AND BILLY R. MARTIN 1046

Species Comparison of Pharmacokinetics and Metal,-olism ofDiltiazem in Humans, Dogs, Rabbits, andRats. POLLEN K. F. YEUNG, SUSAN J. MOSHER,MICHAEL A. QUILLIAM, AND TERRENCE J.MONTAGUE 1055

Pharmacokinetics of Flobufen and its Main Active Me-

tabolite in the Rat. ROMAN LAPKA, STANISLAV

SMOLIK, AND VACLAV REJHOLE 1060

In Vitro Metabolism of Cannabichromene in Seven

Common Laboratory Animals. N. K. BROWN AND

D. J. HARVEY 1065

Systemic Pharmacokinetics of Acetylenic Retinoids inRats. S. S. LIU, R. SANDRI, AND D. D. S. TANG-

LIU 1071

The Pharmacokinetics of (-)-Carbovir in Rats: Evi-dence For Nonlinear Elimination. KENNETH R.BROUWER, ROBERT L. ST. CLAIRE, JEANNE LA-

GARDE, JIM PATANELLA, JOHN WALSH, AND GER-

ALD T. MIWA 1078

The Metabolism and Excretion of Carbovir, a Carbo-

cyclic Nucleoside, in the Rat. JOHN S. WALSH,JAMES E. PATANELLA, STEVE E. UNGER, KENNETH

BROUWER, AND GERALD T. MIWA 1084


Identification of a Glucuronide Conjugate of the Car-bocyclic Nucleoside, Carbovir, Isolated from Mar-moset Urine. JAMES E. PATANELLA, JOHN S.WALSH, STEVE E. UNGER, GERALD T. MIWA, P.SIMON PARRY, MICK J. DANIEL, AND GARY L.EVANS 1092

Identification of Phenolic Doxepin Glucuronides fromPatient Urine and Rat Bile. YUE-ZHONG SHU,JOHN W. HUBBARD, GORDON MCKAY, AND KA-

MAL K. MIDHA 1096

Characterization of a Quaternary, N-Glucuronide Me-tabolite of the Imidazole Antifungal, Tioconazole.P. V. MACRAE, M. KINNS, F. S. PULLEN, AND M.H. TARBIT 1100

The Metabolism of Ofloxacin in Humans. F. A. WONGAND S. C. FLOR 1103

The Metabolic Fate of 13-cis-Retinoic Acid in MouseSkin Microsomal Preparations. NEIL OLDFIELD.. 1105

Author Index 1108

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