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Relationship between phenytoin and tolbutamide hydroxylations in human liver microsomes.
Author(s) -
Doecke CJ,
Veronese ME,
Pond SM,
Miners JO,
Birkett DJ,
Sansom LN,
McManus ME
Publication year - 1991
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.1991.tb05499.x
Subject(s) - tolbutamide , phenytoin , microsome , pharmacology , endocrinology , chemistry , medicine , biochemistry , epilepsy , diabetes mellitus , enzyme , psychiatry
1. The metabolic interaction of phenytoin and tolbutamide in human liver microsomes was investigated. 2. Phenytoin 4‐hydroxylation (mean Km 29.6 microM, n = 3) was competitively inhibited by tolbutamide (mean Ki 106.2 microM, n = 3) and tolbutamide methylhydroxylation (mean Km 85.6 microM, n = 3) was competitively inhibited by phenytoin (mean Ki 22.6 microM, n = 3). 3. A significant correlation was obtained between phenytoin and tolbutamide hydroxylations in microsomes from 18 human livers (rs = 0.82, P less than 0.001). 4. Sulphaphenazole was a potent inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values of 0.4 microM and 0.6 microM, respectively. 5. Mephenytoin was a poor inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values greater than 400 microM 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.