RELATIONSHIP BETWEEN PHENYTOIN AND TOLBUTAMIDE HYDROXYLATIONS IN HUMAN LIVER-MICROSOMES

1 The metabolic interaction of phenytoin and tolbutamide in human liver microsomes was investigated. 2 Phenytoin 4-hydroxylation (mean K(m) 29.6-mu-M, n = 3) was competitively inhibited by tolbutamide (mean K(i) 106.2-mu-M, n = 3) and tolbutamide methylhydroxylation (mean K(m) 85.6-mu-M, n = 3) was competitively inhibited by phenytoin (mean K(i) 22.6-mu-M, n = 3). 3 A significant correlation was obtained between phenytoin and tolbutamide hydroxylations in microsomes from 18 human livers (r(s) = 0.82, P < 0.001). 4 Sulphaphenazole was a potent inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values of 0.4-mu-M and 0.6-mu-M, respectively. 5 Mephenytoin was a poor inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values greater than 400-mu-M for both reactions. 6 Anti-rabbit P450IIC3 IgG inhibited both phenytoin and tolbutamide hydroxylations in human liver microsomes by 62 and 68%, respectively. 7 These in vitro studies are consistent with phenytoin 4-hydroxylation and tolbutamide methylhydroxylation being catalysed by the same cytochrome P450 isozyme(s) in human liver microsomes.