DRUG METABOLISM AND DISPOSITION:

the biological fate of chemicalsKenneth C. Leibman, Editor

Editorial Advisory Board

M. W. Anders Henry M. Fales Donald Perrier

John E. Baer Alberto Frigerio Russell A. Prough

John R. Bend James M. Fujimoto Robert J. Roberts

Frank J. Bullock Theodore E. Gram Morton A. Schwartz

Arthur K. Cho Ernest Hodgson Don W. Shoeman

Dominick Cinti Howard B. Hucker Bitten Stripp

Edward Cone David Kupfer Samson Symchowicz

C. E. Cook Walter G. Levine Elliot S. Vesell

Jerome Edelson Gerhard Levy William J. Waddell

Franz Oesch

Board of Publications Trustees

James A. Bain, Chairman Norman Kirschner Paul L. Munson

Daniel L. Azarnoff Kenneth C. Leibman Irwin M. Weiner

Marion deV. Cotten Gilbert J. Mannering Norman Weiner

Walter Modell

Executive Officer

Houston Baker

January/February 1978 Vol. 6, No. 1

CONTENTSHepatic Monooxygenase Activity and Hepatocellular Morphology in Chickens

Treated with 3-Methylcholanthrene. S. J. BUYNITZKY, A. E. WADE, J. F.MUNNELL, AND W. L. RAGLAND

Absorption and Disposition of Oxarbazole in Man and Laboratory Animals.DAVID BENZIGER, SALLY DORRBECKER, THOMAS GOEHL, AND JEROME EDEL-

SON 8N-Acetylation of Drugs: A Genetically Controlled Reciprocal Relationship be-

tween Drug N-Acetylating Enzymes of Rabbit Liver and Peripheral Blood

Cells. R. R. SZABADI, C. A. MCQUEEN, G. S. DRUMMOND, AND W. W.WEBER 16

The Metabolism and Elimination of Cimetidine, a Histamine H.2-Receptor Antag-onist, in the Rat, Dog, and Man. DONALD C. TAYLOR, PETER R. CRESSwELL,

AND DAVID C. BARTLETU 21The Metabolism of a-Aminobenzolbjthiophene-3-propionic Acid (the Sulfur

Analog of Tryptophan) in the Rat. TALMAGE R. BOSIN, REX G. BICKERS,

ANDALAN DINNER 31Identification of the Metabolites of Trichlorocarbanilide in the Rat. JAMES T.

WARREN, REBECCA ALLEN, AND DEAN E. CARTER 38A Relationship between the Metabolism of Bumetanide and Its Diuretic Activity

in the Rat. STEVEN C. HALLADAY, DEAN E. CARTER, AND I. GLENN SIPES 45

Absorption, Metabolism, and Excretion of ‘4C-Tosifen in the Dog and Rat. C.

LIN, R. FOESTER, J. Lisi, T. Hsu, J. B. MORTON, AND S. SYMCHOWICZ 50

Continued on page 2

Published bi-monthly by The Williams & Wilkins Co., 428 E. Preston St.. Baltimore, Md. 21202,

U.S.A. Subscription price $40.00 per year individuals, $50.00 institutions, single issue $7.00.

Copyright © 1978 by the American Society for Pharmacology and Experimental TherapeuticsSecond class postage pending at Baltimore, Maryland, and at additional mailing offices

Made in the United States of America

Role of the Enterohepatic Circulation in the Elimination of Phenytoin in the Rat.A. MONAEM EL-HAWARI AND GABRIEL L. PL� 59

Excretion of Phenytoin into Semen of Rabbits and Man: Comparison with Plasma

Levels. BRIAN N. SWANSON, REGINA M. LEGER, WILLIAM P. GORDON,

ROBERT K. LYNN, AND NICHOLAS GERBER 70Disposition of Primidone, Phenylethylmalonamide, and Phenobarbital in the

Rabbit. RICHARD J. HUNT AND KENNETH W. MILLER 75The Disposition of threo-a-(2-Piperidyl)-2-trifluoromethyl-6-(4-trifluoromethyl-

phenyl)-4-pyridinemethanol Phosphate in Mice. Ho CHUNG, HAROLD H.GILLUM, AND ROBERT S. ROZMAN 82

Age-dependent Renal Accumulation of Cephaloridine in the Rabbit. J. S. WOLD

AND S. A. TURNIPSEED 87Distribution and Excretion of Chlordecone (Kepone) in the Rat. JOHN L. EGLE,

JR., SUZANNE B. FERNANDEZ, PHILIP S. GUZELIAN, AND JOSEPH F. BORZEL-

LECA 91Rat Hepatic Microsomal Cytochrome(s) P-450 Induced by Polybrominated Bi-

phenyls. JOHN G. DENT, CLIFFORD R. ELCOMBE, KARL J. NETFER, AND

JAMES E. GIBSON 96

Note. Metabolism of Meseclazone in Man. SYD H. DROMGOOLE, KENNETH E.NYMAN, DANIEL E. FURST, WILFRED A. KOLMAN, AND HAROLD E. PAULUS 102

Current Literature 105

Announcements 108

DRUG METABOLISM AND DISPOSITION:

the biological fate of chemicalsInformation for Subscribers

Published bimonthly, one volume per year.

Annual Subscription Rates - U. S. A. AND POSSESSIONS: personal, $40.00; institu-

tional, $50.00. FOREIGN: personal, $43.00; institutional, $53.00. Institutional (multi-

ple-reader) rate applies to libraries, schools, hospitals, group practices, and federal,

commercial, and private institutions and organizations.

Single issues when available, $7.00 in U.S.A., $7.50 elsewhere. Vol 1, No. 1, the Sym-

posium on Microsomes and Drug Oxidations is not available as a single issue of the jour-

nal. It may be purchased as a bound book for $30.00.

Change of address: Publisher must be notified 60 days in advance.

New subscriptions and renewals are entered to begin with the January issue.

Subscriptions should be renewed promptly. The publisher cannot guarantee to supply

back issues on belated renewals.

Correspondence on business matters should be addressed to the publisher.

Reprints of individual articles are available only from authors.

Microfilm: For availability, inquire of The Williams & Wilkins Company.

Instructions to Authors are published in the January-February issue of each volume, or

a copy may be obtained from the Editor, Dr. Kenneth C. Leibman, Box J-267, College

of Medicine, University of Florida, Gainesville, Fla. 32610.

THE WILLIAMS & WILKINS COMPANY428 East Preston Street Baltimore, Maryland 21202 U. S. A.

DRUG METABOLISM AND DISPOSITION:

the biological fate of chemicalsKenneth C. Leibman, Editor

Editorial Advisory Board

M. W. Anders Henry M. Fales Donald Perrier

John E. Baer Alberto Frigerio Russell A. Prough

John R. Bend James M. Fujimoto Robert J. Roberts

Frank J. Bullock Theodore E. Gram Morton A. Schwartz

Arthur K. Cho Ernest Hodgson Don W. Shoeman

Dominick Cinti Howard B. Hucker Bitten Stripp

Edward Cone David Kupfer Samson Symchowicz

C. E. Cook Walter G. Levine Elliot S. Vesell

Jerome Edelson Gerhard Levy William J. Waddell

Franz Oesch

Board of Publications Trustees

James A. Bain, Chairman Norman Kirschner Paul L. Munson

Daniel L. Azarnoff Kenneth C. Leibman Irwin M. Weiner

Marion deV. Cotten Gilbert J. Mannering Norman Weiner

Walter Modell

Executive Officer

Houston Baker

March/April 1978 Vol. 6, No. 2

CONTENTSMetabolism of 5-Isopropyl-1-methyl-2-nitro-1H-imidazole: Identification of Some

Urinary Metabolites in the Dog. A. ASSANDRI, A. PERAZZI, L. F. ZERILLI, P.FERRARI, AND E. MARTINELLI 109

Formation of Sulfone Metabolites from Chlorpromazine and Perazine in Man.

URSULA BREYER-PFAFF, HANNELORE KREFT, HANNELORE RASSNER, AND

AXELPROX 114

Comparison of Biliary Excretory Function and Bile Composition in Male, Female,

and Lactating Female Rats. CURTIS D. KLAASSEN AND STEPHEN C. STROM 120The Disposition of 3-Deazauridine in Mice. RICHARD L. CYSYK, PAUL E.

GORMLEY, MARY ELLEN D’ANNA, AND RICHARD H. ADAMSON 125Dihydropyrimidinase: Stereochemistry of the Metabolism of some 5-Alkylhydan-

toins. KENNETH H. DUDLEY AND SUSAN B. ROBERTS 133

Dihydropyrimidinase: Metabolism of Some Cyclic Imides of Different Ring Size.

JAMES H. MAGUIRE AND KENNETH H. DUDLEY 140

Metabolism and Tissue Distribution of Mono-2-ethylhexyl Phthalate in the Rat. IH

CHU, DAVID C. VILLENEUVE, VIATEUR SECOURS, CLAIRE FRANKLIN, GAIL

ROCK, ANDANDRE VIAU 146Species, Sex, and Developmental Differences in the 0- and N-Dealkylation of

Ethylmorphine by Hepatic Microsomes. DONALD E. NERLAND AND GILBERT

J. MANNERING 150

Metabolism and Disposition of �‘-Tetrahydrocannabinol by the Isolated Perfused

Rabbit Lung. FRANCIS C. P. LAW 154

Continued on ;age 2

Published bi-monthly by The Williams & Wilkins Co., 428 E. Preston St., Baltimore, Md. 21202,

U.S.A. Subscription price $40.00 per year individuals, $50.00 institutions, single issue $7.00.

Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Second class postage pending at Baltimore, Maryland, and at additional mailing offices

Made in the United States of America

Levodopa Pharmacokinetics: Alterations after Benserazide, a Decarboxylase

Inhibitor. H. J. DOLLER, J. D. CONNOR, D. R. LOCK, R. S. SLOVITER, B. H.DVORCHIK, AND E. S. VESELL 164

Biotransformation Products of 3,4,4’-Trichlorocarbanilide in Rat, Monkey, and

Man. C. G. BIRCH, R. A. HILES, T. H. EICHHOLD, A. R. JEFFCOAT, R. W.HANDY, J. M. HILL, S. L. WILLIS, T. R. HESS, AND M. E. WALL 169

The Absorption, Excretion, and Biotransformation of 3,4,4’-Trichlorocarbanilide

in Humans. RICHARD A. HILES AND C. GRANT BIRCH 177Metabolism of Cyclobenzaprine in the Dog. H. B. HUCKER, A. J. BALLETrO, H.

ARISON, AND A. G. ZACCHEI 184Pharmacokinetic Model of Presystemic Metabolism. WAYNE A. COLBURN AND

MIL0 GIBALDI 193In Vivo Evaluation of Michaelis-Menten Constants of Hepatic Drug-Eliminating

Systems: A Commentary. K. SANDY PANG, MALCOLM ROWLAND, AND

THOMAS N. TOZER 197Current Literature 201Announcements 204

DRUG METABOLISM AND DISPOSITION:

the biological fate of chemicalsInformation for Subscribers

Published bimonthly, one volume per year.

Annual Subscription Rates-U. S. A. AND POSSESSIONS: personal, $40.00; institu-

tional, $50.00. FOREIGN: personal, $43.00; institutional, $53.00. Institutional (multi-

ple-reader) rate applies to libraries, schools, hospitals, group practices, and federal,

commercial, and private institutions and organizations.

Single issues when available, $7.00 in U.S.A., $7.50 elsewhere. Vol. 1 , No. 1, the Sym-

posium on Microsomes and Drug Oxidations is not available as a single issue of the jour-

nal. It may be purchased as a bound book for $30.00.

Change of address: Publisher must be notified 60 days in advance.

New subscriptions and renewals are entered to begin with the January issue.

Subscriptions should be renewed promptly. The publisher cannot guarantee to supply

back issues on belated renewals.

Correspondence on business matters should be addressed to the publisher.

Reprints of individual articles are available only from authors.

Microfilm: For availability, inquire of The Williams & Wilkins Company.

Instructions to Authors are published in the January-February issue of each volume, or

a copy may be obtained from the Editor, Dr. Kenneth C. Leibman, Box J-267, College

of Medicine, University of Florida, Gainesville, Fla. 32610.

THE WILLIAMS & WILKINS COMPANY428 East Preston Street Baltimore, Maryland 21202 U. S. A.

DRUG METABOLISM AND DISPOSITION:

the biological fate of chemicalsKenneth C. Leibman. Editor

l:ditorial 4 dvisorv Board

M. W. Anders Henry M. Fales Donald Perrier

John E. Baer Alberto Frigerio Russell A. ProughJohn R. Bend James M. Fujimoto Robert J. Roberts

Frank J. Bullock Theodore E. Gram Morton A. Schwartz

Arthur K. Cho Ernest Hodgson Don W. Shoeman

Dominick Cinti Howard B. Hucker Bitten Stripp

Edward Cone David Kupfer Samson Symchowicz

C. E. Cook Walter G. Levine Elliot S. Vesell

Jerome Edelson Franz Oesch William J. Waddell

Board of Publications Trustees

James A. Bain, Chairman Norman Kirschner Paul L. Munson

Daniel L. Azarnoff Kenneth C. Leibman Irwin M. Weiner

Eva King Killam Gilbert J. Mannering Norman WeinerWalter Modell

Executive Officer

Houston Baker

May/June 1978 Vol. 6, No. 3

CONTENTSStudies on Metabolism of Bromazepam. VI. Reduction of 2-(2-Amino-5-bromoben-

zoyl)pyridine, a Metabolite of Bromazepam, in the Rabbit, Rat, and Guinea

Pig. HIDEO SAWADA AND AK1RA HARA 205

Metabolism of Levorotary 4,5-Dihydrodiazepam in the Rat. L. OTV#{246}S,Zs. TEGYEY,L. VERECZKEY, M. LEDNICZKY, J. TAMAS, E. PAL0sI, AND L. SZPORNY 213

Organic Compounds: Their Interaction with and Degradation of Hepatic MicrosomalDrug-metabolizing Enzymes in Vitro. KATHRYN M. IVANETICH, SHARON Lu-CAS, JULIA A. MARSH, MELANIE R. ZIMAN, I. DEBRA KATZ, AND JEAN J.BRADSHAW . . 218

Microsomal N-Hydroxylation of trans-4’-Alkoxy-4-acetamidostilbenes. R. E. GAM-MANS, R. D. SEH0N, M. W. ANDERS, AND P. E. HANNA 226

Microsomal Mixed-function Amine Oxidase: Oxidation Products of Piperazine-sub-stituted Phenothiazine Drugs. SAMIR S. SOFER AND DANIEL M. ZIEGLER ... 232

Postnatal Development of Phenytoin Metabolic Activity in Rat Liver Microsomes.DAVID A. BLAKE, FRANCES COHEN, AND BARBARA C. MIYASAKI . 240

Influence of Pregnancy and Folic Acid on Phenytoin Metabolism by Rat LiverMicrosomes. DAVID A. BLAKE, JERRY M. COLLINS, BARBARA C. MIYASAKI,

AND FRANCESCOHEN . . . .. . . . 246Phenytoin Metabolism in the Rat: Pharmacokinetic Correlation between in Vitro

Hepatic Microsomal Enzyme Activity and in Vivo Elimination Kinetics. JERRY

M. COLLINS, DAVID A. BLAKE, AND PATRICIA G. EGNER . . 2512,3,7,8-Tetrachlorodibenzofuran in a Commercially Available 99% Pure Polychlori-

Continued on page 2

PuhIi�hed ht-monthI� h� The WiIIiam� & Wilkins Co.. 428 F. Preston St.. Baltimore. Md. 21202.

U.S.A. Subscription price $40.00 per year individuals. $50.0() institutions, single issue $7.00.

Copyright � 1978 by the American Society for Pharmacology and Experimental Therapeutics

Second class postage pending at Baltimore, Maryland, and at additional mailing offices

Made in the United State.s of A merica

nated Biphenyl Isomer Identified as the Inducer of Hepatic Cytochrome P-448and Aryl Hydrocarbon Hydroxylase in the Rat. JOYCE A. GOLDSTEIN, J.

RONALD HASS, PATRICIA LINKO, AND DONALD J. HARVAN .. . 258

Biiary Excretion of N,N-Dimethyl-4-aminoazobenzene in the Rat: Effects of Pre-treatment with Inducers and Inhibitors of the Mixed-function Oxidase System

and with Agents that Deplete Liver Glutathione. WALTER G. LEVINE AND

THEODORE T. FINKELSTEIN 265Biotransformation and Bioactivation of 7, 12-Dimethylbenz(ajanthracene in Human

Fetal and Placental Tissues: Analyses of HPLC Profiles and Studies withSalmonella typhimurium. M. R. JUCHAU, M. J. NAMKUNG, A. H. JONES, AND J.DIGIOVANNI 273

Alterations in the Pharmacokinetics of 3H-�9-Tetrahydrocannabinol in Mice byBacterial Endotoxin. B. R. MARTIN, J. MONTGOMERY, W. L. DEWEY, AND L.

S. HARRIS . . . . . 282

Quantitation of N-Demethylantipyrine in Biological Samples and Isolation andCharacterization of Its Glucuronic Acid Conjugate. C. E. HIGNITE, C. TSCHANZ,

D. H. HUFFMAN, AND D. L. AZARNOFF .. 288

Urinary Metabolites of 3,5-Di-(l-[’3C]methyl-l-methylethyl)-4-hydroxytoluene(BHT-’3C) in Man. L. I. WIEBE, J. R. MERCER, AND A. J. RYAN . . 296

The Metabolism of(2-Cyclopentyl-6,7-dichloro-2-methyl-l-oxo-5-indanyloxy)aceticAcid in Chimpanzee and Man. A. 0. ZACCHEI, T. I. WISHOUSKY, B. H.ARISON, AND 0. HITZENBERGER . . . 303

The Physiological Disposition of (2-Cyclopentyl-6,7-dichloro-2-methyl-1-oxo-5-in-danyloxy)acetic Acid in the Rat, Dog, Rhesus Monkey, and Baboon. A. G.ZACCHEI, T. I. WISHOUSKY, AND L. S. WATSON 313

Elimination of Radioactivity following Administration of [l5,l6-tHlNaltrexone toRats and Guinea Pigs. THOMAS M. LUDDEN, MOHINDER S. BATHALA, LouIsMALSPEIS, MARY A. DRUM, AND RICHARD H. REUNING 321

Lipid-soluble Inhibitors of Dihydrofolate Reductase. I. Kinetics, Tissue Distribution,and Extent of Metabolism of Pyrimethamine, Metoprine, and Etoprine in theRat, Dog, and Man. J. C. CAVALLITO, C. A. NICHOL, W. D. BRENCKMAN, JR.,

R. L. DEANGELIS, D. R. STICKNEY, W. S. SIMMONS, AND C. W. SIGEL 329Pharmacokinetics and Steady-state Myocardial Uptake of Disopyramide in the Dog.

A. KARIM, C. KooK, R. L. NOVOTNEY, J. ZAGARELLA, AND J. CAMPION 338Note. Placental and Milk Transfer of Disopyramide and Metabolites. A. KARIM, C.

KOOK, AND J. CAMPION 346Current Literature 349

Announcements 351

DRUG METABOLISM AND DISPOSITION:

the biological fate of chemicalsKenneth C. Leibman, Editor

Editorial Advisory Board

M. W. Anders Henry M. Fales Donald Perrier

John E. Baer Alberto Frigerio Russell A. Prough

John R. Bend James M. Fujimoto Robert J. Roberts

Frank J. Bullock Theodore E. Gram Morton A. Schwartz

Arthur K. Cho Ernest Hodgson Don W. Shoeman

Dominick Cinti Howard B. Hucker Bitten Stripp

Edward Cone David Kupfer Samson Symchowicz

C. E. Cook Walter G. Levine Elliot S. Vesell

Jerome Edelson Franz Oesch William J. Waddell

Board of Publications Trustees

James A. Bain, Chairman Norman Kirschner Paul L. Munson

Daniel L. Azarnoff Kenneth C. Leibman Irwin M. Weiner

Eva King Killam Gilbert J. Mannering Norman Weiner

Walter Modell

Executive Officer

Houston Baker

July/August 1978 Vol. 6, No. 4

CONTENTSChromatographic and Electrophoretic Heterogeneity of the Cytochromes P-450

Solubiized from Untreated Rat Liver. MARGARET WARNER, MARIO VELLALAMARCA, AND ALLEN H. NEIMS 353

Deuterium Isotope Effects on the Metabolism and Toxicity of Phenacetin in Ham-sters. S. D. NELSON, W. A. GARLAND, J. R. MITCHELL, Y. VAISHNAV, C. N.STATHAM, AND A. R. BUCKPITT 363

The Biotransformation of p-Xylene to a Toxic Aldehyde. J. M. PATEL, C. HARPER,

AND R. T. DREW 368Microsomal Metabolism of Cyclohexene: Hydroxylation in the Allylic Position.

KENNETH C. LEIBMAN AND ELSA ORTIZ 375Metabolism of Thioacetamide and Thioacetamide-S-oxide by Rat Liver Microsomes.

WILLIAM R. PORTER AND ROBERT A. NEAL 379

Synthesis and Characterization of Glucuronides of 5’-Hydroxy-�9-tetrahydrocanna-

binol and 11 -Hydroxy-�9-tetrahydrocannabinol. SHARON PALLANTE, MICHAELA. LYLE, AND CATHERINE FENSELAU 389

In Vitro Metabolism of Phenylacetone, Phenyl-2-butanone, and 3-Methyl-l-phenyl-2-butanone by Rabbit Liver Preparations. R. CRAIG KAMMERER, ARTHUR K.CHO, AND JOHN JONSSON 396

Reductive Metabolism of Nitrofurantoin in the Rat. MICHEL B. AUFRERE, BETTY-

ANN HOENER, AND MARY VORE . . 403

Differential Effects of Walker 256 Carcinosarcoma Cells Growing Subcutaneously,Intramuscularly, or Intraperitoneally on Hepatic Microsomal Mixed-function

Oxygenase Activity. N. E. SLADEK, B. E. DOMEYER, R. L. MERRIMAN, AND G.T. BROPHY 412

Continued on page 2

Published bi-monthly by The Williams & Wilkins Co.. 428 E. Preston St., Baltimore, Md. 21202,U.S.A. Subscription price $40.00 per year individuals, $50.00 institutions, single issue $7.00.

Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Second class postage paid at Baltimore, Maryland, and at additional mailing offices

Made in the United States of America

The Fate of a Major Biliary Metabolite of Digitoxin in the Rat Intestine. R. F. VOLPANDG.L.LAGE 418

Metabolism of Benzo[ajpyrene by the Isolated Perfused Rabbit Lung. BRIAN R.SMITH, RICHARD M. PHILPOT, AND JOHN R. BEND . . . . 425

Binding of Iophenoxate and Iopanoate to Human Serum Albumin. GILBERT H.MUDGE, NORMAN DESBIENS, AND GEORGE R. STIBITZ . . 432

Competition for Binding to Multiple Sites of Human Serum Albumin for Cholecys-tographic Agents and Sulfobromophthalein. GILBERT H. MUDGE, GEORGE R.STIBITZ, MARGARET S. ROBINSON, AND MARK W. GEMBORYS 440

Prolonged Impairment of the Plasma-Protein Binding of Phenytoin in the Rat aftera Single Dose of Sodium Oleate. WAYNE A. COLBURN AND MIL0 GIBALDI 452

Effect of Microsomal Enzyme Inducers on 2,3,7,8-Tetrachlorodibenzo-p-dioxin-in-

duced Depression in the Biliary Excretion of Ouabain in Rats. NoBuKoHAMADA AND RICHARD E. PETERSON . . 456

Disposition of 4,5-Diphenyl-2-oxazolepropionic Acid (Oxaprozin) in Beagle Dogsand Rhesus Monkeys. FRANK W. JANSSEN, SANDRA K. KIRKMAN, JOHN A.KNOWLES, AND HANS W. RUELIUS . . . 465

The Fate of [7-3H]Isoproterenol in Cats after Intravenous Administration. D. KADAR,A. J. LOVRICS, AND L. ENDRENYI 476

0-Methylated Catechol-like Metabolites of Propranolol in Man. T. WALLE, E. C.CONRADI, U. K. WALLE, AND T. E. GAFFNEY . 481

Comparative Metabolism of Hydrocodone in Man, Rat, Guinea Pig, Rabbit, andDog. E. J. CONE, W. D. DARWIN, C. W. GORODETZKY, AND T. TAN . 488

Characterization of Glucuronide Metabolites of Carbamazepine in Human Urine byGas Chromatography and Mass Spectrometry. R. K. LYNN, R. G. SMITH, R.M. THOMPSON, M. L. DEINZER, D. GRIFFIN, AND N. GERBER 492

Note. Formation of Carbamazepine Epoxide in Human Fetal Liver. KENNETH M.PIAFSKY AND ANDERS RANE 502

Current Literature . ... 504

DRUG METABOLISM AND DISPOSITION:

the biological fate of chemicalsInformation for Subscribers

Published bimonthly, one volume per year.

Annual Subscription Rates-U. S. A. AND POSSESSIONS: personal, $40.00; institu-

tional, $50.00. FOREIGN: personal, $43.00; institutional. $53.00. Institutional (multi-

ple-reader) rate applies to libraries, schools, hospitals, group practices, and federal,

commercial, and private institutions and organizations.

Single issues when available, $7.00 in U.S.A., $7.50 elsewhere. Vol. 1, No. 1 ,the Sym-

posium on Microsomes and Drug Oxidations is not available as a single issue of the jour-

nal. It may be purchased as a bound book for $30.00.

Change of address: Publisher must be notified 60 days in advance.

New subscriptions and renewals are entered to begin with the January issue.

Subscriptions should be renewed promptly. The publisher cannot guarantee to supply

back issues on belated renewals.

Correspondence on business matters should be addressed to the publisher.

Reprints of individual articles are available only from authors.

Microfilm: For availability, inquire of The Williams & Wilkins Company.

Instructions to Authors are published in the January-February issue of each volume, or

a copy may be obtained from the Editor, Dr. Kenneth C. Leibman, Box J-267, College

of Medicine, University of Florida, Gainesville, Fla. 32610.

THE WILLIAMS & WILKINS COMPANY428 East Preston Street Baltimore, Maryland 21202 U. S. A.

DRUG METABOLISM AND DISPOSITION:

the biological fate of chemicalsKenneth C. Leibman, Editor

Editorial Advisory Board

M. W. Anders Henry Ni. Fales Donald Perrier

John E. Baer Alberto Frigerio Russell A. Prough

John R. Bend James M. Fujimoto Robert J. Roberts

Frank J. Bullock Theodore E. Gram Morton A. Schwartz

Arthur K. Cho Ernest Hodgson Don W. Shoeman

Dominick Cinti Howard B. Hucker Bitten Stripp

Edward Cone David Kupfer Samson Symchowicz

C. E. Cook Walter G. Levine Elliot S. Vesell

Jerome Edelson Franz Oesch William J. Waddell

Board of Publications Trustees

Norman Weiner, Chairman Norman Kirschner Walter Modell

Daniel L. Azarnoff Kenneth C. Leibman Paul L. Munson

Eva King Killam Gilbert J. Mannering Irwin M. Weiner

Executive Officer

Houston Baker

September/October 1978 Vol. 6, No. 5

CONTENTS3,4,5-Trimethoxybenzoic Acid, a New Mescaline Metabolite in Humans. LOTHAR

DEMISCH, PETER KACzMARCzYK, AND NIKOLAUS SElLER 507

Species Differences in the Disposition and Metabolism of 6.1 l-Dihydro-1 1-oxodi-benz(be�oxepin-2-acetic acid (Isoxepac) in Rat, Rabbit, Dog. Rhesus Mon-

key, and Man. H. P. A. ILLING AND J. M. FROMSON 510

Biotransformation of Methyl 5-Cyclopropylcarbonyl-2-benzimidazolecarbamate

(Ciclobendazole) in Rats and Dogs. B. C. MAYO, R. R. BRODIE, L. F.CHASSEAUD,ANDD.R.HAWKINS 518

Comparative Physiological Disposition of Ellipticine in Several Animal Species

After Intravenous Administration. MARJORY CHADWICK, DENISE M. SIL-

vEIRA, BARBARA B. PLATz, AND DENISE HAYES 528

Characterization of the Metabolites of Ellipticine in Rat Bile. ALAN R. BRANF-

MAN. ROBERT J. BRUNI, VERNON N. REINHOLD, DENISE M. SILvEIRA,

MARJORY CHADWICK, AND DAVID W. YESAIR 542

Metabolism of Aniline in Rats, Pigs. and Sheep. J. KAO, J. FAULKNER, AND J. W.BRIDGES 549

Metabolism of Haloforms to Carbon Monoxide. II. In Vivo Studies. M. W.ANDERS. J. L. STEVENS. R. W. SPRAGUE. Z. SHAATH. AND A. E. AHMED 556

Factors Affecting the Metabolism of [4C]Acetylhydrazine in Rats. JAMES M.WRIGHT AND JOHN A. TIMBRELL 561

Complications in the Estimation of Hepatic Blood Flow In Vivo by Pharmacoki-

netic Parameters: The Area Under the Curve after the Concomitant Intrave-

nous and Intraperitoneal (or Intraportal) Administration of Acetaminophen

in the Rat. K. SANDY PANG AND JAMES R. GILLETrE 567

Continued on page 2

Published bi-monthly by The Williams & Wilkins Co.. 428 E. Preston St., Baltimore, Md. 21202,

U.S.A. Subscription price $40.00 per year individuals, $50.00 institutions, single issue $7.00.

Copyright © 1978 by the American Society for Pharmacology and Experimental TherapeuticsSecond class postage paid at Baltimore, Maryland, and at additional mailing offices

Made in the United States of America

The Postnatal Development of Microsomal Epoxide Hydrase, Cytosolic Glutathi-one S-Transferase, and Mitochondrial and Microsomal Cytochrome P-450 in

Adrenals and Ovaries of Female Rats. HASAN MUKHTAR, RICHARD M.PHILPOT, AND JOHN R. BEND 577

Structural Requirements for the Accumulation of Chlorinated Biphenyl Metabo-lites in the Fetal Rat Intestine. G. W. LUCIER, 0. S. MCDANIEL, C. M.

SCHILLER, AND H. B. MATrHEWS 584Metabolism of Methimazole by Rat Liver Cytochrome P-450-containing Monoxy-

genases. PHILIP W. LEE AND ROBERT A. NEAL 591

Partial Purification and Characterization of Dihydropyrimidinases from Calf andRat Liver. JAMES H. MAGUIRE AND KENNETH H. DUDLEY 601

Current Literature 606Announcements 609, 610

Correspondence. Assay of Hepatic Microsomal Hexobarbital Hydroxylase. DAVID

KUPFER 610

DRUG METABOLISM AND DISPOSITION:

the biological fate of chemicalsIn formation for Subscribers

Published bimonthly, one volume per year.

Annual Subscription Rates-U. S. A. AND POSSESSIONS: personal, $40.00; institu-

tional, $50.00. FOREIGN: personal, $43.00; institutional, $53.00. Institutional (multi-

ple-reader) rate applies to libraries, schools, hospitals, group practices, and federal,

commercial, and private institutions and organizations.

Single issues when available, $7.00 in U.S.A., $7.50 elsewhere. Vol. 1, No. 1 ,the Sym-

posium on Microsomes and Drug Oxidations is not available as a single issue of the jour-

nal. It may be purchased as a bound book for $30.00.

Change of address: Publisher must be notified 60 days in advance.

New subscriptions and renewals are entered to begin with the January issue.

Subscriptions should be renewed promptly. The publisher cannot guarantee to supply

back issues on belated renewals.

Correspondence on business matters should be addressed to the publisher.

Reprints of individual articles are available only from authors.

Microfilm: For availability, inquire of The Williams & Wilkins Company.

Instructions to Authors are published in the January-February issue of each volume, or

a copy may be obtained from the Editor, Dr. Kenneth C. Leibman, Box J-267, College

of Medicine. University of Florida, Gainesville, Fla. 32610.

THE WILLIAMS & WILKINS COMPANY428 East Preston Street Baltimore, Maryland 21202 U. S. A.

DRUG METABOLISM AND DISPOSITION:

the biological fate of chemicalsKenneth C. Leibman. Editor

Editorial A dvisorv Board

M. W. Anders Henry M. Fales Donald Perrier

John E. Baer Alberto Frigerio Russell A. Prough

John R. Bend James M. Fujimoto Robert J. Roberts

Frank J. Bullock Theodore E. Gram Morton A. Schwartz

Arthur K. Cho Ernest Hodgson Don W. Shoeman

Dominick Cinti Howard B. Hucker Bitten Stripp

Edward Cone David Kupfer Samson Svmchowicz

C. E. Cook Walter G. Levine Elliot S. Vesell

Jerome Edelson Franz Oesch William J. Waddell

Board of Publications Trustees

Norman Weiner, Chairman Norman Kirschner Walter Modell

Daniel L. Azarnoff Kenneth C. Leibman Paul L. Munson

Eva King Killam Gilbert J. Mannering Irwin M. Weiner

Executive OfficerHouston Baker

November/December 1978 Vol. 6, No. 6

CONTENTSConjugation of Various Drugs in Isolated Hepatocytes. Bo ANDERSSON, MARGARETA

BERGGREN, AND PETER MOLDEUS 611Stereoselectivity in the Metabolism of the Enantiomers of Cyclophosphamide in

Mice, Rats, and Rabbits. PETER J. Cox, PETER B. FARMER, MICHAEL JARMAN,

RYSZARD W. KINAS, AND WOJCIECH J. STEC 617a-Methyldopamine, a Key Intermediate in the Metabolic Disposition of 3,4-Meth-

ylenedioxyamphetamine in Vivo in Dog and Monkey. K. K. MIDHA, J. W.HUBBARD, K. BAILEY, AND J. K. COOPER 623

Rabbit Hepatic Microsomal 0-Demethylation of Chlorotrianisene. PETER C. RUEN-

ITZ 631Pharmacokinetics of Sul.fadimidine in Normal and Diarrheic Calves. ROMAN LAPKA,

ZDENA URBANOVA, BO�IDAR KOBYLKA, HELENA RA�KOVA, JiftI VANE�EK, AND

LADISLAV POLAK . . . . 637Evaluation of Succinimidoethyl and Pivaloyloxyethyl Esters as Progenitors of Meth-

yldopa in Man, Rhesus Monkey, Dog, and Rat. S. VICK.ERS, C. A. DUNCAN, S.D. WHITE, G. 0. BR.EAULT, R. B. ROYDS, P. J. DE SCHEPPER, AND K. F. TEMPERO 640

Biotransformation of Prochiral 2-Phenyl-l,3-di(4-pyndyl)-2-propanol to a Chiral N-

Oxide Metabolite. MORTON A. SCHWARTZ, THOMAS H. WILLIAMS, STANLEY J.KOLIS, EDWARD POSTMA, AND GINO J. SAsso 647

The Absorption, Distribution, and Excretion in Mice of the Antimalarial Mefloquine,erythro-2,8-Bis(trifluoromethyl)-a-(2-piperidyl)-4-quinolinemethanol Hydro-chloride. ROBERT S. ROZMAN, NICHOLAS A. MOLEK, AND ROBERT KOBY 654

Physiological Disposition and Metabolism of Cyclobenzaprine in the Rat, Dog,Rhesus Monkey, and Man. H. B. HUCKER, S. C. STAUFFER, A. J. BALLETTO, S.D. WHITE, A. G. ZACCHEI, AND B. H. ARISON

Continued on page 2

Published bi-monthly by The Williams & Wilkins Co.. 428 E. Preston St.. Baltimore. Md. 21202.

U.S.A. Subscription price $40.00 per year individuals. $50.00 institutions, single issue $7.00.

Copyright © 1978 by the American Society for Pharmacology and Experimental TherapeuticsSecond class postage paid at Baltimore, Maryland. and at additional mailing offices

Made in the United States of A merica

N-Didemethyl-n-propionyl-6,9; 9,12-erythromycin A-spiroketal, a New Metabolite

of Erythromyci.n Ethyl Succinate in Man. J. MAJER, R. S. STANASZEK, S. L.MUELLER, AND G. MARTI . 673

Enzymatic Conjugation and Hydrolysis of ‘80-Isoborneol Glucuronide. LESLIE P.

JOHNSON AND CATHERINE FENSELAU 677Note. Effects of Phenobarbital and 3-Methylcholanthrene on Anesthetic Defluon-

nation in Fischer 344 Rats. RICHARD I. MAZZE AND BEN HIrr 680

Current Literature 682Author Index . . .. . 685Subject Index . . . 688

DRUG METABOLISM AND DISPOSITION:

the biological fate of chemicalsInformation for Subscribers

Published bimonthly. one volume per year.

Annual Subscription Rates - U. S. A. AND POSSESSIONS: personal. $40.00; institu-

tional. $50.00. FOREIGN: personal. $43.00; institutional. $53.00. Institutional (multi-

ple-reader) rate applies to libraries, schools, hospitals. group practices. and federal,

commercial, and private institutions and organizations.

Single issues when available. $7.00 in U.S.A.. $7.50 elsewhere. Vol. 1. No. I .the Sym-

posium on Microsomes and Drug Oxidations is not available as a single issue of the jour-

nal. It may be purchased as a bound book for $30.00.

Change of address: Publisher must be notified 60 days in advance.

New subscriptions and renewals are entered to begin with the January issue.

Subscriptions should be renewed promptly. The publisher cannot guarantee to supply

back issues on belated renewals.

Correspondence on business matters should he addressed to the publisher.

Reprints of individual articles are available onl from authors.

Microfilm: For availability, inquire of The Williams & Wilkins Company.

Instructions to Authors are published in the January-February issue of each volume, or

a copy may he obtained from the Editor. Dr. Kenneth C. Leibman. Box J-267. College

of Medicine. University of Florida, Gainesville. Fla. 32610.

THE WILLIAMS & WILKINS COMPANY428 East Preston Street Baltimore. Maryland 21202 U. S. A.