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Vol. 28, Issue 8, 865-868, August 2000

SHORT COMMUNICATION
CYP2C8/9 Mediate Dapsone N-Hydroxylation at Clinical Concentrations of Dapsone

Helen R. Winter, Yi Wang, and Jashvant D. Unadkat

Department of Pharmaceutics,
University of Washington,
Seattle, Washington

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-Menten Km 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 cytochrome b5-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.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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