The oxidative metabolism of tolbutamide was studied in 13 healthy subjects of known debrisoquine phenotype. Three were poor (PM) and ten were extensive (EM) metabolisers of debrisoquine. The mean values for total plasma clearance, elimination half-life, and metabolic clearance were 0.26 ml.min-1.kg-1, 3.4 h, and 0.17 ml.min-1. kg-1 in PM subjects and 0.22 ml.min-1.kg-1, 4.3 h and 0.15 ml.min-1.kg-1 in EM subjects. Total urinary recovery (% of dose) and ratio of hydroxy- to carboxytolbutamide were 69.4% and 0.219 respectively in PM subjects and 70.9% and 0.226 in EM subjects. There were no statistically significant differences between EM and PM metabolisers for any of these parameters. In addition there was no correlation between the debrisoquine metabolic ratio and tolbutamide urinary metabolite recovery or plasma clearance. These data indicate that hydroxylation of debrisoquine and tolbutamide are not catalyzed by the same enzyme. The ratio of hydroxy- to carboxytolbutamide in our subjects, and in other recent studies, suggests that some previous publications were inaccurate and their conclusions about the genetic control of tolbutamide metabolism were incorrect.

Ten normal subjects of known debrisoquin phenotype (six extensive (EM) and four poor (PM) metabolizers) were given of 5 mg glyburide (glibenclamide) suspension orally. Plasma glyburide and urinary cis-3-hydroxy-(30H) and trans-4-hydroxyglyburide (40H) were measured by a sensitive HPLC assay. No unchanged glyburide was detected in urine but both metabolites were identified in urine in all subjects. There were no significant differences in any respect with regard to glyburide metabolism or pharmacokinetics between EM and PM of debrisoquin. Estimated mean elimination half-life of glyburide was 3.3 +/- 1.1 hours for EM and 2.5 +/- 0.4 hours for PM. In one subject (EM), with reduced excretion of 30H, glyburide was detected in plasma at 24 and 30 hours and the apparent elimination half-life was 9.3 hours. There was no significant difference for total metabolite recovery between EM and PM. Eight of the subjects (six EM and two PM) had previously taken part in a study of tolbutamide metabolism, and a comparison of metabolic clearances by hydroxylation for the two sulfonylurea drugs showed no significant correlation. Glyburide is therefore unlikely to be metabolized by the enzymes that metabolize either debrisoquin or tolbutamide.

1 The standard laboratory method for determination of debrisoquine phenotype has been modified and shortened with no loss of sensitivity. Debrisoquine metabolic ratios (MR) at 4 and 8 h showed excellent correlation indicating that collection time can also be shortened. Same day phenotyping is therefore possible. 2 One hundred normal, Caucasian Australian subjects were phenotyped (46 males, 54 females) and 6% were poor metabolisers (PM) of debrisoquine. 3 Fifty of the original subjects were also acetylation phenotyped and 34% were fast and 66% slow acetylators. One PM of debrisoquine was a fast acetylator of sulphadimidine and four PM were slow acetylators. This was a non-significant association.