Cotrimoxazole as an inhibitor of oxidative drug metabolism: effects of trimethoprim and sulphamethoxazole separately and combined on tolbutamide disposition.

Abstract

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 < 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 < 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 < 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.

Trimethoprim and Sulfamethoxazole are Selective Inhibitors of CYP2C8 and CYP2C9, Respectively

“…However, most previous clinical drug-drug interaction studies involving trimethoprim have focused on substrates of CYP2C9. For example, trimethoprim used alone inhibited the metabolic clearance of tolbutamide (14%) and phenytoin (30%) (Hansen et al, 1979;Wing and Miners, 1985). As can be seen from Figs.…”

“…It has been suggested that inhibition of oxidative drug metabolism by trimethoprim and sulfamethoxazole is the likely mechanism of these drug-drug interactions (Wing and Miners, 1985). In previous in vitro studies, sulfamethoxazole has been shown to inhibit tolbutamide hydroxylation (a CYP2C9 marker reaction) with an apparent K i value of about 250 M (Back et al, 1988;Komatsu et al, 2000a).…”

“…Trimethoprim and sulfamethoxazole have increased the plasma concentrations or effects of drugs such as tolbutamide, phenytoin, warfarin, and glipizide, resulting in clinically significant drug-drug interactions (Hansen et al, 1979;O'Reilly, 1980;Wing and Miners, 1985;Johnson and Dobmeier, 1990). It has been suggested that inhibition of oxidative drug metabolism by trimethoprim and sulfamethoxazole is the likely mechanism of these drug-drug interactions (Wing and Miners, 1985).…”

Considerations when prescribing trimethoprim-sulfamethoxazole

“…[26][27][28][29][30]65 However, sulfamethoxazole itself can directly cause pancreatic insulin release, particularly at higher doses and in patients with renal impairment. 25 This likely reflects the drug's structural similarity to the sulfonylureas.…”

“…64 Pharmacokinetic studies have shown that trimethoprim-sulfamethoxazole increases plasma levels of sulfonylureas 65 and repaglinide, 26 leading to an increased release of pancreatic insulin and symptomatic hypoglycemia. 27,28 The clinical consequences of the interaction between trimethoprimsulfamethoxazole and sulfonylureas have been described in case reports and observational studies, which have reported four-to sixfold increases in the risk of hospital admission for hypoglycemia following the addition of trimethoprimsulfamethoxazole to regimens containing a sulfonylurea.…”