Hepatic metabolism of tolbutamide: characterization of the form of cytochrome P-450 involved in methyl hydroxylation and relationship to in vivo disposition

RG Knodell, SD Hall, GR Wilkinson and FP Guengerich

In vitro investigations suggest the same human liver cytochrome P-450 that catalyzes S-mephenytoin 4-hydroxylation, P-450MP, is responsible for methyl hydroxylation of the oral hypoglycemic agent tolbutamide. Tolbutamide hydroxylase activity copurified with P-450MP; electrophoretically homogenous P-450MP catalyzed both tolbutamide and S- mephenytoin hydroxylation. Each substrate competitively inhibited hydroxylation of the other, and anti-P-450MP inhibited tolbutamide hydroxylation in human liver microsomes. Significant correlation between tolbutamide and S-mephenytoin hydroxylase activities was seen in a set of human liver samples. These findings suggested that subjects with a genetically determined impairment in ability to hydroxylate mephenytoin might also have deficient tolbutamide metabolism. However, plasma tolbutamide concentration-time profiles and urinary excretion of metabolites formed via the hydroxylation pathway were similar in four phenotypically poor and six extensive metabolizers of mephenytoin. We suggest that alteration of a substrate binding site of P-450MP may reduce its ability to hydroxylate S-mephenytoin but not tolbutamide.

Volume 241, Issue 3, pp. 1112-1119, 06/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics

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