Announcements

Johananoff International Fellowship for Advanced Biomedical Studies

The Mario Negri Institute Foundation, Inc. invites of the directions in which research in the area should applications for the 1976-77 Johananoff International be pursued. The report will be given as a lecture and Fellowship for Advanced Biomedtcal Studies. The Fel- will be published as a book or review article. The stipend low will spend a sabbatical year at the Mario Negri is $15,000, which may be supplemented by the Fellow’s Institute for Pharmacological Research in Milan, read- home institution or from other sources. ing, ttnnking, and writing, and producing an advanced Applications containing curriculum vitae, list of publi- study on a chosen topic. Eligible candidates are those cations, pertinent reprints, and an outline (about 250 non-Itlian citizens from academic, governmental, or words) of the proposed study, must be mailed by Janu- nonprofit institutions who are actively engaged in re- ary 28, 1976. The award will be announced on March search in, and have made outstanding contributions to, 30, 1976, and the Fellow must begin his year’s tenure one of the following fields: cancer chemotherapy and/or within calendar year 1976. For further information, immunology, cardiovascular pharmacology. neuropsy- address the Johananoff Fellowship Committee, Istituto chopharmacology, or drug metabolism. The report to be di Ricerche Farmacologiche “Mario Negri,” Via Eritrea prepared will be a critical analysis of the status of knowl- 62. 20157 Milan, Italy. edge in a well defined area, with a prospective summary

Symposium-workshop on Mutagenesis/Drug Metabolism

Feb. 9-10, 1976 (tentative), Research Triangle Park, search Triangle Park, NC. 27709. For registration, give N.C. Cosponsored by National Institute of Environ- name, address, phone number, affiliation, nature of your mental Health Sciences and Division of Drug Metab- interest in the conference, and information on data, if olism, ASPET. Attendance limited to 250. Some volun- any, which you wish to present. Acceptance of registra- teered papers on metabolic activation of mutagens and tion implies a moral commitment to attend, due to the promutagens can be accepted. Information and ad- limitations on accommodations; please do not register vanced registration: Dr. Frederick de Serres or Dr. unless you have every intention of attending. James R. Fouts, NIEHS, Post Office Box 12233, Re-

5th European Workshop on Drug Metabolism

June 14-18. 1976, Stockholm, Sweden. Cosponsored tutet. Information: Dr. Hans Selander, Apotekarsociete- by Swedish Academy of Pharmaceutical Sciences and ten, Box 1136, S-lIl8I Stockholm, Sweden. Department of Forensic Medicine, Karolinska Insti-

591 DRUG METABOLISM AND DISPOSITION

Vol. 3 No. 6 Copyright #{174}1975 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A

Editorial Acknowledgment

Essential to the success of any journal that attempts to maintain a high scholarly level of reporting of scientific research is the quality of the evaluation accorded to the submitted manuscripts. The editor is utterly dependent upon those who review these manuscripts, and all his efforts would come to naught without the devoted and conscientious service given by the reviewers. This editor shall always be grateful for the willing and excellent way in which reviewers have accepted and discharged these very time-consuming duties. A large share of the total chore is accomplished by the members of the Editorial Advisory Board, but much welcome help has come from many other members of the scientific community. The editor acknowledges with many thanks the contributions of the following scientists, each of whom has reviewed one or more manuscripts for DRUG METABOLISM AND DISPOSITION: the biologica! fate of chemicals during the first three years of its existence.

Alvito Alvares J. Gaylor Dirk K. F. Meijer Aaron H. Anton Harry V. Gelboin James A. Miller Irwin M. Arias Nicholas Gerber J. R. Mitchell Steven D. Aust J. R. Gillette Salvatore J. Mule Billy Baggett Avram Goldstein Thomas F. Muther Jeffrey Baron McChesney Goodall Robert A. Neal David Bickers Donald L. Grant Daniel W. Nebert Alexander Black J. T. Groves Philip Needleman William Bousquet Anthony M. Guarino Gary L. Neil Edward Bresnick I. C. Gunsalus Franz Oesch Gary Brooker Corwin Hansch Vincent T. Oliverio Frank J. Bullock Charles Heidelberger C. W. Parker Thomas C. Butler J. A. Himes R. E. Parks, Jr. Vincent P. Butler G. H. Hitchings C. J. Parli Paul Calabresi D. W. H. Ho John P. Perkins Sungman Cha Jordan L. Holtzman Donald Perrier Marjory Chadwick Elizabeth Jeffrey Julian Peterson Dominick Cinti Donald M. Jerina Richard Peterson Ellis N. Cohen David Jollow Gabriel L. Plaa Burton Combes M. R. Juchau Curtis Porter Edward Cone W. J. Jusko Russell A. Prough C. E. Cook Georg F. KahI Anders Rane M. J. Coon H. Kalant Ronald E. Rasmussen C. Cornelius Sumner M. Kalman Marcus Reidenberg William A. Creasey M. A. Q. Khan Herbert Remmer J. T. Doluisio Curtis D. Klaassen R. H. Reuning H. Wyman Dorough Robert Krooth Edward S. Reynolds Jacques Dreyfuss Ronald G. Kuntzman Robert J. Roberts Jerome Edelson Harvey J. Kupferberg Malcolm Rowland Thomas E. Eling G. L. Lage Robert J. Rubin Gertrude Elion G. A. LePage Daniel M. Rudman Ronald W. Estabrook Wayne Levin Lewis S. Schanker Larry Fischer Walter G. Levine Ronald R. Scheline Jack Fishman Charles L. Litterst John Schenkman James R. Fouts Robert J. Luchi Morton Schwartz Michael R. Franklin G. W. Lucier David Shand Melvin Fried Daniel S. Lukas D. W. Shoeman Alberto Frigerio Roger P. Maickel S. G. Sipes James M. Fujimoto Gilbert J. Mannering S. Sisenwine Raymond L. Furner Bettie Sue Masters R. L. Smith Thomas Gaffney H. B. Matthews Thomas W. Smith 592 EDITORIAL ACKNOWLEDGMENT 593

Robert Snyder Dominick J. Tocco Grant R. Wilkinson Bela Solymoss George Torosian Kenneth I. Williams R. D. Stewart David M. Travis R. T. Williams Robert E. Stitzel Russell A. Van Dyke Shen K. Yang Clement A. Stone A. E. Wade S. Y. Yeh James A. Straw E. L. Way D. W. Yesair Bitten Stripp Wendell Weber David Zakim Richard C. Thomas Richard Welch V. Zannoni Vera Thomas C. F. Wilkinson E. A. Zeller AUTHOR INDEX

Abbott, R. L, 309 Drew,R.T.,38l Aksamit, W., 467 Duncan, A. E. W., 361 Allen, J. G., 332 East, P. B., 332 Alton, K. B., 352, 445 Edelson, J., 520 Alvin, J. D., 345 El-Bassiouni, E. A., 543 Anders, M. W., 104 El-Hawey, A. M., 171 Anderson, J. H., 275 Eling, T. E., 389 Anderson, M. W., 211, 371, 389 Faraj, B. A., 226 Arinc, E., 118 Fischer, L. J., I Arison, B. H., 80, 189 Fouts, J. R., 118, 254, 381 Atallah, Y. H., 513 Francis, R. J., 332 Balletto, A. J., 80 Fritz, A., 520 Benziger, D., 520 Fukazawa, H., 235 Berry, D. 1., 494 Gaertner, H. J., 437 Bertele, R., 437 Gammans, R. E., 266 Bognacki, J., 220 Gessner, T., 407 Boobis, A. R., 63 Gingell, R., 42 Breault, G. 0., 453 Gorodetzky, C. W., 417 Breyer, U., 437 Gram, T. E., 259 Bryan, G. T., 89 Gregory, P. A., 287 Burke, M. D., 245 Grimes, R. M., 352 Bush, M. T., 345 Gruber, V. F., 189, 361 Busigny, M., 133 Haigh, J. L., 332 Carter, C. J. K., 309 Hamada, N., 407 Chando, T. J., 96 Harper, C., 381 Chang, R. L., 487 Hintze, K. L., I Cheripko, J. A., 297 Ho, D. H. W., 309 Chinn, 1. J., 467 Holtzman,J, L., 113 Chiu, C. W., 89 Horning, M. G., 47, 287 Claeys, A. E., 423 Hribar, J., 467 Cohen, A. M., 303 Hucker, H. B., 80, 361 Cone, E. J., 417 Hunter, A. L., 530 Congiu, L., 148 Ichishita, H., 235 Conney, A. H., 502 Inaba, T., 69, 479 Corongiu, F. P., 148 Israili, Z. H., 198, 226 Coutinho, C. B., 297 Iwase, H., 235 Crabtree, R. E., 164 Joly, J.-G., 577 Crew, MC., 10 Juchau, M. R., 494 Cucinell, S. A., 283 Kalow, W., 479 Cruyl, A. A., 423 Kappus, H., 338 Davison, C., 520 Karim, A., 467 Dayton, P. G., 30, 198, 226, 283 Kau, S. 1., 345 Dean, A. V., 171 Kellermann, G., 47 Dean, M. E., 325 Kimmel, H. B., 180 de Ia Iglespa, F., 10 Klaassen, C. D., 530 Dc Leenheer, A. P., 423 Klausner, H. A., 314 deLuna, F. A., 361 Kostenbauder, H. B., 557 Demetriades, J., 80 Kubic, V. L., 104 de Sagher, R. M., 423 Kupferberg, H. J., 26 Devereux, T. R., 254 Lan, S. J., 96, 171 Di Carlo, F. J., 10 Lawrence, R. 5., 74 Dingell. J. V., 314 Lech, J. J., 400 Doherty, M., 467 Leibman, K. C., 507 Dorough, H. W., 513 Levin, W., 502 Doyon, C., 577 Levine, R. R., 525

594 AUTHOR INDEX 595

Levine, W. G., 220 Ruelius, H. W., 85, 180 Lin, C., 487 Ryan, J., 297 Liomin, G., 437 Sanna, A., 148 Litterst, C. L., 259 Schillings, R. T.. 85 Liu, A. L., 180 Schreiber, E. C.. 96, 171 Loo, T. L., 309 Schwartz, M. A., 297 Lubawy, W. C., 557 Schwartz, M. H., 85 Lucek, R. W., 297 Seifert, J., 430 Luyten-Kellermann, M., 47 Shah, K. R., 74 Marchand, C., 565 Shah, N. S., 74 Marshall, F. J., 155 Shaw, C., 352, 445 Matthews, H. B., 211. 371 Shimizu, H., 235 Mayer, R. T., 245 Sinsheimer, J. E., 15 McBride, C. M., 309 Sisenwine, S. F., 85, 180 McGuire, J. L., 352, 445 Somani, S. M., 275 McMahon, R. E., 155, 164 Squires, C., 525 McNay, J. L., 30 Stafford, M., 47 Mehendale, H. M., 543 Statham, C. N., 400 Meijer, D. K. F., 220 Stavchansky, S. A., 557 Mimnaugh. E. G.. 259 Steelman, S. L., 453 Mitchell, L., 10 Stern, I. J., 536 Mu, J. Y.. 198 Sternson, L. A.. 266 Murphy. P. J., 155. 164 StilIwell, W. G., 287 Nadeau, D., 565 Stock, B. H., 325 Namkung, M. J., 494 Sumner, D. D., 283 Neely, A. E., 74 Takizawa, T., 235 Ortiz, E., 507 Tang, B. K., 479 Orton,T.C., 389 Thompson, J. A., 113 Pani, P., 148 Thorstenson, J. H., 513 Patrick, J. E., 352, 445 Titus, D. C., 189 Pepple. S. K., 400 Tocco, D. J., 361, 453 Perrier, C. V., 453 Umeda, T., 69 Pesant, Y., 577 V#{226}cha,J., 430 Philpot, R. M., 118 VandenHeuvel, W. J. A., 189, 361 Pickett, R. D., 389 Van Dyke, R. A., SI Plostnieks, J., 283 Villumsen, D., 437 Poppcrs. P. J., 502 Wang, C. Y., 89 Porter, C. C., 189 Wang, Z.-Y. J., 536 Pottier, J., 133 Walsh, C. T., 525 Powis, G., 63 Wilcox, H. G.. 314 Pruitt, A. W.. 30, 226 Williams, T. L., 155, 164 Rama Sastry. B. V., 345 Wold,J.S., I Raynaud. J. P.. 133 Wood, C. L., SI Reagan, R. L., 259 Yonekawa, W., 26 Reif, V. D., 15 Zacchei, A. G., 80, 453 Remmer, H., 338 Zampaglione, N., 487 Ridolfo, A. S., 164 Zachariah, P. K., 494 SUBJECT INDEX

Acetaminophen, hydrolysis, effect of metyrapone, 507 Carbon tetrachioride Acetanilide hydroxylation, effect on, of metyrapone effectson hexobarbital sleeping-times, 148 and related compounds, 507 hepatotoxicity, protection against by lead nitrate, Acetophenone, effect on anilide hydroxylation, 507 148 Acetylacetone, derivatization with, ofamidino groups, Central nervous system transport, of triamterene, 30 332 Centrifugation, microsomal losses during, correction 2-Acetylaminofluorene, metabolism in placental and for, 577 fetal tissue, 494 Chlorobiphenyl (s), disposition, 371 Aidrin, disposition by perfused lung, 543 Cigarette smoke, biological fate of insecticide residues Amidino groups, derivatization with acetylacetone, from, 513 332 Colchicine, biliary excretion and toxicity, 530 Amiloride, transport in central nervous system, 30 Conjugation, taurine, of substituted phenylacetic Aminopyrine N-demethylase, induction by bro- acids, 171 mazepam, 235 Cumene hydroxide, drug oxidation supported by, 245 Amobarbital, N-hydroxylation of, in man, 479 Current Literature, 58, 127, 230, 320, 419, 587 Aniline, metabolism and disposition, in perfused liver, Cyclocytidine, metabolism and disposition, in dog, 309 63 p-(Cyclopropylcarbonyl)phenylacetic acid, metab- Aniline hydroxylase, induction by bromazepam, 235 olism, species differences, 171 Antimalarial(s), quinolinemethanol, disposition and Cyproheptadine metabolism, 198 epoxide metabolite, I Antipyrine half-life, correlation with aryl hydrocarbon metabolism in man, 189 hydroxylase of lymphocytes, 47 Cytochrome(s), purified, biphenyl hydroxylation by, Arabinosylcytosine, disposition in dog, 309 245 Artifact(s),control of, in drug metabolism, 417 Cytochrome P-448 Aryl hydrocarbon hydroxylase purified in fetal and placental tissues, 494 ethoxyresorufin de-ethylation by, 245 in human lymphocytes, correlation with drug specificities, 245 metabolism, 47 Cytochrome P-450 fraction, from rabbit lung, 118 Benzene, hydroxylation, in lung and liver microsomes, measurement, in homogenates, 577 381 purified, specificities, 245 Benzphetamine, demethylation, in reconstituted rabbit lung system, 118 DDA Benzpyrene, metabolism, in placental and fetal tissue, biliary excretion, 42 494 enterohepatic circulation of, 42 Benzpyrene, hydroxylase, induction, in mice, 502 o, p’-DDD, metabolism, 15 Biphenyl (s), polychlorinated, disposition, 371 DDT Biphenyl hydroxylation, by purified cytochromes, 245 metabolism, 42 Bromazepam, induction of microsomal enzymes by, residues from cigarette smoke, biological fate of, 235 513 Debrisoquin sulfate, metabolism, 332 Carbaryl Deoxycorticosterone, effect,on liver and lung drug biliary metabolites, in trout, 400 metabolism, 254 residues from cigarette smoke, biological fate of, N-Desmethylmedazepam, metabolism, in rat, 297 513 Dexamethasone, effect, on liver and lung drug metab- Carbofuran, residues from cigarettesmoke, biological olism, 254 fate of, 513 Diazepam, metabolism, in rat, 297 Carbon dioxide, metabolism, by propionic acid, 155 Diazoxide, metabolism and disposition (review), 226 Carbon monoxide Dibromomethane, metabolism to carbon monoxide, competition, for reduced cytochrome P-450, with 104 nitro compounds, 266 24-(2,2Dichlorocyclopropyl)phenoxy-2-methy1pro- production, from dihalomethanes, 104 panoic acid, disposition, 520

596 SUBJECT INDEX 597

Dieldrin, disposition, by perfused lung, 543 Imipramine, accumulation, in isolated perfused lung, 5-(2’,4’-Difiuorophenyl)salicylic acid, metabolism 389 and disposition, 453 Insecticide, residues from cigarette smoke, biological Dihalomethane, metabolism to carbon monoxide, 104 fate of, 513 N,N-Dimethylaniline, metabolism, in lung micro- Iproclozide, hydrazide cleavage, in man, 423 somes, effect of pregnancy on, 254 Isomorphine, production, artifactual, from mor- Diphenyihydantoin phine, 417 biliary excretion, 69 metabolite, interaction with other substrates, 557 Kidney, drug metabolism, species differences, 259 a ,a’-Dipyridyl, effect on anilide hydroxylation, 507 Kidney transport, of triamterene, 30

Lauryl sulfate, metabolism, 164 Epoxide metabolite(s) of cyproheptadine, I Lead nitrate of protriptyline, 80 effects, on hexobarbital sleeping times, 148 Errata, 57, 131, 233, 590 protection by, against carbon tetrachloride hepato- Erythromycin, metabolism, 155 toxicity, 148 Ethanol, effect on methadone absorption, 525 Leptophos, residues from cigarette smoke, biological 7-Ethoxycoumarin, de-ethylation, in reconstituted fate of, 513 rabbit lung system, 118 Lipoprotein, plasma, binding of tetrahydrocannabinol Ethoxyresorufin, de-ethylation, by purified cyto- by, 314 chrome P448, 245 Liver, perfused, metabolism of griseofulvin in, 487 Extrahepatic drug metabolism, species differences, 259 Lorazepam, glucuronidation, in cats, 85 Lung drug metabolism, species differences, 259 Fetal metabolism, of benzpyrene and 2-acetylamino- microsomes, drug metabolism, effect of pregnancy fluorene, 494 on, 254 Floctafenin, metabolism and disposition, 133 perfused 5-Fluorouracil, metabolite of ftorafur, 303 disposition of aidrin and dieldrin by, 543 Fluphenazine, metabolite accumulation, 437 imipramine accumulation in, 389 Formanilide, metabolism, effect of metyrapone and rabbit, reconstitution of mixed function oxidase related compounds, 507 components, 118 Ftorafur, disposition, in rats, 303 Medazepam, metabolism, in rat, 297 Gastrointestinal absorption, of methadone, 525 Mefioquine, disposition and metabolism, 198 Glucuronidation, in perfused liver, 407 Mephenytoin, metabolism and activity, 26 Glucuronide, formation, in cat, 85 Mescaline, distribution, in developing rat, 74 Griseofulvin, metabolism, 487 Metabolic activation, norethisterone, 338 Metabolite binding, in liver, from halothane, 51 Halothane, metabolite binding in liver, 51 Methadone, gastrointestinal absorption, 525 Hepatotoxicity, carbon tetrachloride, protection Methanesulfonanilide, metabolism, effect of metyra- against by lead nitrate, 148 pone and related compounds, 507 a-Hexachlorocyclohexane, effect on, pyrimidine Methaqualone, metabolites, in man and rat, 287 synthesis, 430 3-Methylcholanthrene Hexobarbital induction, of phenacetin and benzpyrene metab- sleeping-time olism in mice, 502 during pregnancy, 325 pretreatment, effect on conjugation in perfused effects on of carbon tetrachloride and lead liver, 407 nitrate, 148 Metyrapone i-Homoannulation, of progestins, 180 competition, for reduced cytochrome P-450, with Hydrazide cleavage, of iproclozide, in man, 423 nitro compounds, 266 Hydrocortisone, effect, on liver and lung drug metab- effect on anilide hydroxylation, 507 olism, 254 Microsomal losses, during centrifugation, correction N-Hydroxyamobarbital, metabolite of amobarbital, for, 577 in man, 479 Microsomes, lung, drug metabolism, effect of preg- Hydroxylation, biphenyl, by purified cytochromes, 245 nancy on, 254 5-(p-Hydroxyphenyl)-5-phenylhydantoin, interaction Milk of Magnesia, effect on methadone absorption, with other substrates, 557 525 3-Hydroxyphenyl-trimethyl ammonium, metabolism, Mitotane, metabolism, 15 in perfused liver, 275 Morphine, artifactual false metabolite, 417 598 SUBJECT INDEX

NADPH, cytochrome c reductase, purification from Progestins rabbit lung, 118 aromatization of, 180 Nafenopin, effect on hepatic uptake and biliary cx- r-homoannulation of, 180 cretion of ouabain, 220 Propionanilide, metabolism, effect of metyrapone Neostigmine, metabolism, in perfused liver, 275 and related compounds, 507 Niflumic acid, microsomal hydroxylation of, 96 Propionic acid, metabolism to carbon dioxide, 155 Nirvanol, metabolism and activity, 26 Propionyl erythromycin, and lauryl sulfate salts, Nitro compounds, difference spectra, with reduced metabolism of, 155 cytochrome P-450, 266 Propionyl erythromycin lauryl sulfate, metabolism, Nitrofurylthiazolylacetamjde, metabolism and dis- 164 position, 89 Protriptyline, epoxide metabolites, 80 p-Nitrophenyl, conjugation, in perfused liver, 407 Pyrimidine, synthesis, effect of a-hexachlorocyclo- Norethisterone, metabolic activation, to protein- hexane on, 430 binding metabolite, 338 Norgestrel, metabolism, stereoselective, in women, Quaternary ammonium compounds, disposition, in 180 perfused liver,275 Quinolinemethanol, antimalarials, disposition and Ouabain, bepatic uptake and biliary excretion, effect metabolism, 198 of nafenopin on, 220 Oxisuran, metabolism, in monkey, 10 Salicylic acid, difluorophenyl-, metabolism and dis- position, 453 Parathion, residues from cigarette smoke, biological SKF 525-A, effect on aniline disposition in perfused fate of, 513 liver, 63 2,4,5,2’, 5’ Pentachlorobiphenyl, disposition, 211 Species differences, extrahepatic drug metabolism, 259 Pentobarbital, R-(+) and S-(-), microsomal metab- Spironolactone, metabolism in man, 467 olism, 113 Sulfacetamide, distribution, in tumor-bearing rat, 565 Perphenazine, metabolite accumulation, 437 Sulfation, in perfused liver, 407 Phenacetin 0-dealkylation, induction, in mice, 502 Phenol, metabolism, in lung and liver microsomes, 381 Taurine, conjugation, of substituted phenylacetic Phenylacetic acid(s), substituted, metabolism, species acids, 171 differences, 171 9-Tetrahydrocannabinol, binding, by plasma lipo- Phenylbutazone half life, correlation with aryl hydro- proteins, 314 carbon hydroxylase of lymphocytes, 47 Timalol, metabolism and disposition, 361 Phospholipid binding, of halothane metabolite, 51 Tolmetin, metabolism, 283 Placental metabolism, of benzpyrene and 2 acetyl- Triamterene aminofluorene, 494 metabolism, in rat, 345 Placental transport, of triamterene, 30 transport, in central nervous system, kidney, Polyoxypropylene-polyoxyethylene copolymer, dis- placenta, 30 position in rat, 536 Triflubazepam, biotransformation, in man, 352 Pregnancy Triflubazam, metabolism, comparative, in rats, dogs, drug metabolism during, in rat, 325 and monkeys, 445 effect Trifluoperazine, metabolite accumulation, 437 on drug metabolism in lung microsomes, 254 Tumor-bearing rat, sulfacetamide distribution in, 565 on liver and lung drug metabolism, 254 on metabolism of N,N-dimethylaniline in lung Walker 256 tumor, sulfacetamide distribution in rats microsomes, 254 bearing, 565 Prochlorperaune, metabolite accumulation, 437 WR 30,090. disposition and metabolism, 198