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Research ArticleArticle

Biotransformation of Nevirapine, a Non-nucleoside HIV-1 Reverse Transcriptase Inhibitor, in Mice, Rats, Rabbits, Dogs, Monkeys, and Chimpanzees

Paul S. Riska, David P. Joseph, Roger M. Dinallo, Walter C. Davidson, James J. Keirns and Susan E. Hattox
Drug Metabolism and Disposition December 1999, 27 (12) 1434-1447;
Paul S. Riska
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David P. Joseph
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Roger M. Dinallo
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Walter C. Davidson
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James J. Keirns
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Susan E. Hattox
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Abstract

The study objectives were to characterize the metabolism of nevirapine (NVP) in mouse, rat, rabbit, dog, monkey, and chimpanzee after oral administration of carbon-14-labeled or -unlabeled NVP. Liquid scintillation counting quantitated radioactivity and bile, plasma, urine, and feces were profiled by HPLC/UV diode array and radioactivity detection. Metabolite structures were confirmed by UV spectral and chromatographic retention time comparisons with synthetic metabolite standards, by β-glucuronidase incubations, and in one case, by direct probe electron impact ionization/mass spectroscopy, chemical ionization/mass spectroscopy, and NMR. NVP was completely absorbed in both sexes of all species except male and female dogs. Parent compound accounted for <6% of total urinary radioactivity and <5.1% of total fecal radioactivity, except in dogs where 41 to 46% of the radioactivity was excreted as parent compound. The drug was extensively metabolized in both sexes of all animal species studied. Oxidation to hydroxylated metabolites occurred before glucuronide conjugation and excretion in urine and feces. Hydroxylated metabolites were 2-, 3-, 8-, and 12-hydroxynevirapine (2-, 3-, 8-, and 12-OHNVP). 4-carboxynevirapine, formed by secondary oxidation of 12-OHNVP, was a major urinary metabolite in all species except the female rat. Glucuronides of the hydroxylated metabolites were major or minor metabolites, depending on the species. Rat plasma profiles differed from urinary profiles with NVP and 12-OHNVP accounting for the majority of the total radioactivity. Dog plasma profiles, however, were similar to the urinary profiles with 12-OHNVP, its glucuronide conjugate, 4-carboxynevirapine, and 3-OHNVP glucuronide being the major metabolites. Overall, the same metabolites are formed in animals as are formed in humans.

Footnotes

  • Send reprint requests to: Dr. Susan Hattox, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877-0368. E-mail: shattox{at}rdg.boehringer-ingelheim.com

  • ↵1 This work has been previously presented in abstract form at meetings, as follows: Riska PS, Joseph DP, Dinallo RP, Hattox SE and Keirns JJ, Metabolism of Nevirapine, A NonNucleoside Reverse Transciptase Inhibitor, in Mouse, Rat, Dog, Rabbit and Monkey, and Riska PS, Lamson MJ, Sabo JP, Hattox SE, and Keirns JJ, Metabolism And Excretion of Nevirapine, A NonNucleoside Reverse Transcriptase Inhibitor, in Man, 7th North American ISSX Meeting, October 20–24, 1996, San Diego, CA.

  • Abbreviations used are::
    NVP
    nevirapine, 5,11-Dihydro-11-cyclopropyl-4-methyl-6H-dipyrido[3,2,-b:2′,3′-e][1,4]diazepin-6-one
    CI
    chemical ionization
    EI
    electron impact ionization
    MS
    mass spectroscopy
    SPE
    solid phase extraction
    Tmax
    time to maximum plasma concentration
    OHNVP
    hydroxynevirapine
    CANVP
    carboxynevirapine
    • Received November 5, 1998.
    • Accepted August 18, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (12)
Drug Metabolism and Disposition
Vol. 27, Issue 12
1 Dec 1999
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Research ArticleArticle

Biotransformation of Nevirapine, a Non-nucleoside HIV-1 Reverse Transcriptase Inhibitor, in Mice, Rats, Rabbits, Dogs, Monkeys, and Chimpanzees

Paul S. Riska, David P. Joseph, Roger M. Dinallo, Walter C. Davidson, James J. Keirns and Susan E. Hattox
Drug Metabolism and Disposition December 1, 1999, 27 (12) 1434-1447;

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Research ArticleArticle

Biotransformation of Nevirapine, a Non-nucleoside HIV-1 Reverse Transcriptase Inhibitor, in Mice, Rats, Rabbits, Dogs, Monkeys, and Chimpanzees

Paul S. Riska, David P. Joseph, Roger M. Dinallo, Walter C. Davidson, James J. Keirns and Susan E. Hattox
Drug Metabolism and Disposition December 1, 1999, 27 (12) 1434-1447;
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