Abstract
Using selective cytochrome P450 (CYP) inhibitors and clinical concentrations (4 μM) of dapsone (DDS), we found a major contribution of CYP2C9 and little or no contribution (≤10%) of CYP3A4 and CYP2E1 to dapsone N-hydroxylation (DDS-NHY) in human liver microsomes. Sulfaphenazole (2.16 μM) and tolbutamide (500 μM), selective inhibitors of CYP2C9 (or 2C8/9), inhibited DDS-NHY by 48 ± 14 and 41 ± 15%, respectively. The apparent Michaelis-MentenKm values for DDS-NHY by cloned CYP2C8, CYP2C9, CYP2C18, and CYP2C19 were 75 μM, 31 μM, 25 μM, and greater than 1 mM, respectively. CYP3A4 and CYP2E1 were incapable of DDS-NHY at 4 μM DDS. S-mephenytoin (360 μM) activated DDS-NHY by human liver microsomes and by CYP2C8 by 43 ± 36 and 193 ± 16%, respectively. This activation was cytochromeb5-dependent. In contrast,S-mephenytoin inhibited DDS-NHY by CYP2C9, CYP2C18, and CYP2C19 by 27 ± 2, 49 ± 1, and 32 ± 4%, respectively. Because CYP2C18 and CYP19 are expressed at low concentrations in the human liver, these observations indicate that at clinical DDS concentrations, CYP2C9 is a major and CYP2C8 is a likely minor contributor to DDS-NHY in human liver microsomes.
Footnotes
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Send reprint requests to: Jashvant D. Unadkat, Ph.D., Department of Pharmaceutics, Box 357610 H272 Health Sciences Building, University of Washington, Seattle, WA 98195-7610. E-mail:jash{at}u.washington.edu.
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This work was supported by NIH AI 27664 from the National Institutes of Health. DDS-HA was synthesized by Starks Associates, Inc. under Contract NO1 A1 050515 from the National Institutes of Health.
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↵1 Abbreviations used are: DDS, dapsone; DDS-NHY, dapsone N-hydroxylation; DDS-HA, dapsoneN-hydroxylamine; DDC, diethyldithiocarbamate; HLM, human liver microsomes; CYP, cytochrome P450.
- Received September 14, 1998.
- Accepted April 14, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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CYP2C8/9 Mediate Dapsone N-Hydroxylation at Clinical Concentrations of Dapsone
