Cotrimoxazole as an inhibitor of oxidative drug metabolism: effects of trimethoprim and sulphamethoxazole separately and combined on tolbutamide disposition.
The effect of separate pretreatments with cotrimoxazole, sulphamethoxazole and trimethoprim on the disposition of tolbutamide was studied in seven healthy males. Tolbutamide 500 mg intravenously was administered on four separate occasions--as a control without pretreatment and on the seventh day of separate twice daily administration of cotrimoxazole (sulphamethoxazole 800 mg plus trimethoprim 160 mg) (ST phase), sulphamethoxazole 1 g (S phase) and trimethoprim 150 mg (T phase). Tolbutamide total and unbound plasma clearance (CL) were reduced following each of the individual pretreatments compared to the control phase (P less than 0.001). For unbound CL the reductions were 14% in the S and T phases and 25% in ST phase. Tolbutamide elimination half-life was prolonged following each pretreatment (P less than 0.001) by 20% in the S phase, 19% in the T phase and 30% in the ST phase. Tolbutamide total steady-state volume of distribution (VSS) was increased by 10% in the S and ST phases (P less than 0.01), the increase being accounted for by an increase in tolbutamide unbound fraction. There was no change in tolbutamide unbound VSS following any of the pretreatments. These results are consistent with inhibition of tolbutamide oxidation by cotrimoxazole, an additive effect of the two components sulphamethoxazole and trimethoprim. Sulphamethoxazole also reduces tolbutamide plasma protein binding.
D000328:Adult; D004338:Drug Combinations / Q000494:pharmacology; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D013420:Sulfamethoxazole / Q000494:pharmacology*; D014044:Tolbutamide / Q000097:blood / Q000378:metabolism*; D014295:Trimethoprim / Q000494:pharmacology*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination
D004338:Drug Combinations; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D014044:Tolbutamide; D014295:Trimethoprim; D013420:Sulfamethoxazole