Abstract
This in vitro study was designed to identify the enzyme(s) involved in the two major metabolic pathways of rokitamycin [formations of leucomycin A7 (LMA7) from rokitamycin and of leucomycin V (LMV) from LMA7] and to assess possible drug interactions using human liver microsomes. Formation of LMA7 or LMV was NADPH-independent. Anti-rat NADPH cytochrome P-450 (CYP) reductase serum, specific inhibitors, or substrates of CYP isoforms showed no effects on the formation of LMA7 or LMV. The meanVmax andVmax/Km for the formation of LMA7 from rokitamycin were much greater (P < .01) than those for the formation of LMV from LMA7. Two esterase inhibitors, bis-nitro-phenylphosphate and physostigmine (100 μM), inhibited the formation of LMA7 or LMV by more than 85%, whereas no appreciable inhibition occurred by several substrates of carboxylesterase (EC 3.1.1.1). Except the moderate inhibition produced by promethazine and terfenadine, theophylline, mequitazine, chlorpheniramine, and diphenhydramine showed little or no inhibition for the formation of LMA7 or LMV. Rokitamycin, LMA7, LMV, erythromycin, and clarithromycin (up to 500 μM) had no appreciable inhibition for CYP1A2-, 2C9-, and 2D6-mediated catalytic reactions. However, rokitamycin, LMA7, erythromycin, and clarithromycin inhibited the CYP3A4-catalyzed triazolam α–hydroxylation with IC50(Ki) values of 5.8 (2.0), 40, 33 (20), and 56 (43) μM, respectively. It is concluded that the formations of LMA7 from rokitamycin and of LMV from LMA7 are catalyzed mainly by human esterase enzyme [possibly cholinesterase (EC3.1.1.8)]. However, whether rokitamycin would inhibit the CYP3A-mediated drug metabolism in vivo requires further investigations in patients.
Footnotes
-
Send reprint requests to: Dr. Takashi Ishizaki, M.D., Ph.D., Department of Pharmacology and Therapeutics, Graduate School of Clinical Pharmacy, Kumamoto University, Oe-honmachi 5–1, Kumamoto 862-0973, Japan.
-
↵1 Current address: Department of Clinical Pharmacology, Research Institute, International Medical Center of Japan, Tokyo, Japan.
-
↵2 Current address: Division of Clinical Pharmacology, Department of Medicine, Wishard Memorial Hospital, Indiana University School of Medicine, Indianapolis, IN 46202-2879.
-
↵3 Current address: Department of Pharmacology and Therapeutics, Graduate School of Clinical Pharmacy, Kumamoto University, Oe-honmachi 5–1, Kumamoto 862-0973, Japan.
-
This study was supported by a grant-in-aid from the Ministry of Human Health and Welfare and by a postdoctoral fellowship training program from the Bureau of International Cooperation, International Medical Center of Japan (Tokyo, Japan).
- Abbreviations used are::
- LMA7
- leucomycin A7
- LMV
- leucomycin V
- CYP
- cytochrome P-450
- BNPP
- bis-p-nitrophenyl phosphate
- SKF-525A
- 2-diethylaminoethyl-2,2-diphenylvalterate
- FMO
- flavin-containing monooxygenase
- Received October 29, 1998.
- Accepted March 1, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
