A screening test for slow metabolisers of tolbutamide.
1. Six subjects participated in a detailed pharmacokinetic study of tolbutamide (pilot study). Using parameters based on these data, sixty-three non-diabetic volunteers underwent a simple screening test designed to identify slow metabolisers of tolbutamide. 2. The screening test was an estimate of tolbutamide plasma elimination half-life from plasma concentrations at 8 and 24 h after 500 mg tolbutamide orally, and urinary recovery of the hydroxy- and carboxytolbutamide metabolites over the 4-8 h post-dose period. 3. The mean tolbutamide half-life for 61 of the screened subjects was 7.5 +/- 1.5 h (range 5.2-12.2 h). Two subjects had half-lives of 21.6 and 16.1 h. Their urinary metabolite recoveries were within the range of those in the screening test but lower than those in the pilot study. 4. The subject with the 21.6 h half-life was restudied with intensive serial sampling for 72 h post-dose. She was confirmed as a 'slow' metaboliser of tolbutamide since her terminal half-life was 25.9 h but plasma Cmax and tmax were within the range of those in the detailed study. This subject's 24 h urinary recoveries of both hydroxytolbutamide and carboxytolbutamide were clearly different from the mean values for the pilot study subjects implicating hydroxylation of tolbutamide as the metabolic defect. 5. The two point plasma half-life is therefore a discriminatory screening test but a 4-8 h urinary recovery is not. 6. A partial family study did not provide conclusive evidence of the inheritance of slow tolbutamide metabolism but the screening test should allow simple identification of slow metabolisers for further study.
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M A
MA
Department of Clinical Pharmacology, Royal North Shore Hospital, NSW, Australia.
Boutagy
J S
JS
Shenfield
G M
GM
D000293:Adolescent; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D012016:Reference Values; D014044:Tolbutamide / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics; D000096926:Benzenesulfonamides
D014044:Tolbutamide; C006913:carboxytolbutamide; C031014:hydroxymethyltolbutamide; D000096926:Benzenesulfonamides