Lack of relationship between tolbutamide metabolism and debrisoquine oxidation phenotype

Abstract

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.

3,4-Dehydrodebrisoquine, a Novel Debrisoquine Metabolite Formed from 4-Hydroxydebrisoquine That Affects the CYP2D6 Metabolic Ratio

“…Since the discovery of the debrisoquine 4-hydroxylation polymorphism almost three decades ago (Mahgoub et al, 1977), there have appeared a host of reports that correlated some aspect of drug disposition with numerical values of the debrisoquine metabolic ratio, with greater or lesser success; for example, with nortriptyline (Mellstrom et al, 1981;Woolhouse et al, 1984), amitriptyline (Mellstrom et al, 1986), phenformin (Oates et al, 1982), sparteine (Inaba et al, 1983), tolbutamide (Peart et al, 1987), and ifosfamide (Philip et al, 1988). It is now clear that the classical metabolic ratio, as used by these various investigators, may not have been the best tool with which to correlate the metabolism of a second substrate.…”

Clinical Pharmacology of Sulfonylureas

“…The enzyme involved in the initial metabolic step seems to be CYP2C9 (VERONESE et al 1990bRELLING et al 1990;VERONESE 1991;LEEMANN et al 1993), whereas no association appears to exist with CYP2D6 (debrisoquine) PEART et al 1987) or CYP2C 18/19 (Smephenytoin) (KNODELL et al 1987;RELLING et al 1990). …”

“…Only subjects with half-lives greater than 20 h may be considered slow metabolizers, which needs to be confirmed, however, by determination of oral plasma clearance or urinary metabolic ratio (VERONESE et al 1990a). The pharmacokinetics of the metabolites is clearly formation dependent (PEART et al 1987). …”

Pharmacokinetics of tolbutamide in ethnic Chinese

“…The subjects studied lived in Australia and had a westernised lifestyle and diet. The tolbutamide pharmacokinetic parameters observed have been compared with those published previously in Caucasians [ 9] and therefore this study also provides insight into the in vivo activity of CYP2C9 in Chinese and Caucasians.…”

“…Tolbutamide is a first generation oral sulphonylurea hypoglycaemic agent, used in the treatment of non‐insulin dependent diabetes. Tolbutamide is eliminated principally by CYP2C9 catalysed metabolism to hydroxytolbutamide, which is in turn further metabolised to carboxytolbutamide by cytosolic alcohol and aldehyde dehydrogenases [ 9]. Despite its declining use in the west, tolbutamide is relatively cheap and is therefore widely used in Asia [ 10] and its use may be predicted to increase due to the rising incidence of diabetes in Orientals [ 11].…”