RT Journal Article
SR Electronic
T1 Hepatic metabolism of tolbutamide: characterization of the form of cytochrome P-450 involved in methyl hydroxylation and relationship to in vivo disposition.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1112
OP 1119
VO 241
IS 3
A1 R G Knodell
A1 S D Hall
A1 G R Wilkinson
A1 F P Guengerich
YR 1987
UL http://jpet.aspetjournals.org/content/241/3/1112.abstract
AB 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.