Metabolism of ketoconazole and deacetylated ketoconazole by rat hepatic microsomes and flavin-containing monooxygenases

Drug Metabolism and Disposition

Volumn 25, Issue 6, 1997, Pages 772-777

  Acosta Jr , Daniel ^a,b   Rodriguez, Rosita J ^c  

^a UNIVERSITY OF CINCINNATI   (United States)

^b UNIVERSITY OF TEXAS AT AUSTIN   (United States)

^c NONE

Author keywords

[No Author keywords available]

Indexed keywords

GLUCOSE 6 PHOSPHATE; KETOCONAZOLE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; UNSPECIFIC MONOOXYGENASE;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; DRUG ACETYLATION; DRUG DEGRADATION; DRUG PROTEIN BINDING; ENZYME ACTIVITY; LIVER CLEARANCE; LIVER MICROSOME METABOLISM; LIVER TOXICITY; NONHUMAN; PRIORITY JOURNAL; RAT;

ANIMALS; ANTIFUNGAL AGENTS; KETOCONAZOLE; MICROSOMES, LIVER; OXYGENASES; RATS; RATS, SPRAGUE-DAWLEY; SWINE;

ANIMALIA; SUS SCROFA;

EID: 0343416836     PISSN: 00909556     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (21)

1. H. Vanden Bossche, P. Marichal, J. Gorrens, H. Geerts, and P. A. Janssen: Basis for the search for new antifungal drugs. Ann. N. Y. Acad. Sci. 544, 191-207 (1988).
2. J. J. Sheets and J. I. Mason: Ketoconazole: a potent inhibitor of cytochrome P-450-dependent drug metabolism in rat liver. Drug Metab. Dispos. 12, 603-606 (1984).
3. C. G. Meredith, A. L. Maldonado, and K. V. Speeg: The effect of ketoconazole on hepatic oxidative drug metabolism in the rat in vivo and in vitro. Drug Metab. Dispos. 13, 156-162 (1985).
4. A. Pont, J. R. Graybill, P. C. Craven, J. N. Galgiani, W. E. Dismukes, R. E. Reitz, and D. A. Stevens: High-dose ketoconazole therapy and adrenal and testicular function in humans. Arch. Intern. Med. 144, 2150-2153 (1984).
5. R. C. Heel, R. N. Brogden, A. Carmine, P. A. Morley, T. M. Speight, and G. S. Avery: Ketoconazole: a review of its therapeutic efficacy in superficial and systemic fungal infections. Drugs 23, 1-36 (1982).
6. Y. C. Huang, J. L. Colaizzi, R. H. Bierman, R. Woestenborghs, and J. Heykants: Pharmacokinetics and dose proportionality of ketoconazole in normal volunteers. Antimicrob. Agents Chemother. 30, 206-210 (1986).
7. J. G. Baxter, C. Brass, J. Schentag, and R. Slaughter: Pharmacokinetics of ketoconazole administered intravenously to dogs and orally as tablet and solution to humans and dogs. J. Pharmaceut. Sci. 75, 443-447 (1986).
8. A. M. Sugar, S. G. Alsip, J. N. Galgiani, J. R. Graybill, W. E. Dismukes, G. Cloud, P. Craven, and D. Stevens: Pharmacology and toxicity of high-dose ketoconazole. Antimicrob. Agents Chemother. 31, 1874-1878 (1987).
9. E. W. Gascoigne, G. J. Barton, M. Michaels, W. Meuldermans, and J. Heykants: The kinetics of ketoconazole in animals and man. Clin. Res. Rev. 1, 177-187 (1981).
10. T. Daneshmend and D. Warnock: Clinical pharmacokinetics of ketoconazole. Clin. Pharmacokinet. 14, 13-34 (1988).
11. L. W. Whitehouse, A. Menzies, B. Dawson, J. Zamecnik, and W. W. Sy: Deacetylated ketoconazole: a major ketoconazole metabolite isolated from mouse liver. J. Pharmaceut. Biomed. Anal. 8, 603-606 (1990).
12. G. Medoff and G. S. Kobayashi: Strategies in the treatment of systemic fungal infections. N. Engl. J. Med. 302, 145-155 (1980).
13. L. W. Whitehouse, A. Menzies, R. Mueller, and R. Pontefract: Ketoconazole-induced hepatic phospholipidosis in the mouse and its association with de-N-acetyl ketoconazole. Toxicology 94, 81-95 (1994).
14. G. Lake-Bakaar, P. J. Scheuer, and S. Sherlock: Hepatic reactions associated with ketoconazole in the United Kingdom. Br. Med. J. 294, 419-422 (1987).
15. B. H. C. Stricker, A. P. R. Blok, F. B. Bronkhorst, G. E. Van Parys, and V. J. Desmet: Ketoconazole-associated hepatic injury a clinicopathological study of 55 cases. J. Hepatol 3, 399-406 (1986).
16. J. R. Cashman and D. M. Ziegler: Contribution of N-oxygenation to the metabolism of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine) by various liver preparations. Mol. Pharmacol. 29, 163-167 (1986).
17. C. Miranda, W. Chung, R. Reed, X. Zhao, M. Henderson, J. Wang, D. Williams, and D. Buhler: Flavin-containing monooxygenase: a major detoxifying enzyme for the pyrrolizidine alkaloid senecionine in guinea pig tissues. Biochem. Biophys. Res. Comm. 178, 546-552 (1991).
18. R. J. Rodriguez and D. Acosta: N-deacetyl ketoconazole-induced hepatotoxicity in a primary culture system of rat hepatocytes. Toxicology 117, 123-131 (1997).
19. L. W. Whitehouse, A. Menzies, B. Dawson, T. Cyr, A. By, D. Black, and J. Zamecnik: Mouse hepatic metabolites of ketoconazole: isolation and structure elucidation. J. Pharmaceut. Biomed. Anal. 12, 1425-1441 (1994).
20. D. M. Ziegler: Recent studies on the structure and function of multisubstrate flavin-containing monooxygenases. Ann. Rev. Pharmacol. Toxicol 33, 179-199 (1993).
21. D. M. Ziegler: Flavin-containing monooxygenases: catalytic mechanism and substrate specificities. Drug Metab. Rev. 19, 1-32 (1988).