Pharmacogenetics of tolbutamide metabolism in humans

Abstract

The genetic control of tolbutamide [used in control of diabetes] disposition in humans was studied, and the potential for high accrued blood levels in individuals receiving fixed dosage regimens was discussed. Tolbutamide was administered i.v. to 42 nondiabetic subjects, 8 of their relatives and to 5 sets of twins. A 9-fold variation in the rate of tolbutamide disappearance from plasma (Kd) was found. This variation was characterized by a trimodal frequency distribution, suggestive of monogenic inheritance and consistent with pedigree analysis, indicating autosomal transmission of rapid and slow inactivation of tolbutamide. A heritability value of 0.995 for Kd indicated little influence of environmental factors on variation of this rate. Interindividual differences in the binding of 35S-tolbutamide to serum proteins were assessed. No correlation was found between tolbutamide serum protein binding affinity and Kd. Analysis of the metabolites of tolbutamide in urine samples provided evidence for the microsomal oxidation of the drug to hydroxytolbutamide as the primary site of genetic control. Evidence for monogenic control of tolbutamide metabolism in man is provided. Fixed dosage regimens of this drug, as prescribed in the controversial University Group Diabetes Program study, might lead to higher accrued blood levels in slow inactivators.