| Autor: |
Knodell, R G, Hall, S D, Wilkinson, G R, Guengerich, F P |
| Zdroj: |
The Journal of Pharmacology and Experimental Therapeutics; June 1987, Vol. 241 Issue: 3 p1112-1119, 8p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
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