Effects of enzyme inducers and inhibitors on the pharmacokinetics of metformin in rats: involvement of CYP2C11, 2D1 and 3A1/2 for the metabolism of metformin

Abstract

Background and purpose: The types of hepatic microsomal cytochrome P450 (CYP) isozymes responsible for the metabolism of metformin in humans and rats have not been published to date. Therefore, a series of experiments using various inducers and inhibitors of CYP isozymes was conducted to find out what types of CYP isozymes are involved in the metabolism of metformin in rats.

Experimental approach: Metformin at a dose of 100 mg kg(-1) was administered intravenously to rats. The rats were pretreated with CYP inducers such as 3-methylcholanthrene, orphenadrine, isoniazid, and dexamethasone (major inducers of CYP1A1/2, 2B1/2, 2E1, and 3A1/2, respectively, in rats), or CYP inhibitors such as SKF-525 (a non-specific inhibitor of CYP isozymes), and sulfaphenazole, quinine, and troleandomycin (major inhibitors of CYP2C11, 2D1, and 3A1/2, respectively, in rats). The time-averaged non-renal clearance (CLNR) of metformin was compared with that of controls.

Key results: In rats pretreated with dexamethasone, the CLNR was significantly faster (57% increase) than for the controls. In rats pretreated with SKF-525-A, sulfaphenazole, quinine, and troleandomycin, the CLNR was significantly slower (24.3, 62.9, 77.6, and 78.7% decrease, respectively) than for the controls. However, the CLNR values did not significantly different in the rats pretreated with 3-methylencholanthrene, orphenadrine, and isoniazid compared with the controls.

Conclusions and implications: Our data suggest that metformin was metabolized mainly via CYP2C11, 2D1, and 3A1/2 in rats. This result could contribute to understanding of the possible changes in metformin pharmacokinetics in disease models where CYP2C11 and/or 3A1/2 are altered.

Figures

Figure 1

Arterial plasma concentration–time profiles of metformin after 1-min i.v. administration at a dose of 100 mg kg−1 to rats pretreated with various enzyme inducers (open circles), 3-methylcholanthrene (a), orphenadrine (b), isoniazid (c) or dexamethasone (d) and their respective control rats (filled circles). Data are presented as mean±s.d.

Figure 2

Arterial plasma concentration–time profiles of metformin after 1-min i.v. administration at a dose of 100 mg kg−1 to rats pretreated with various enzyme inhibitors (open circles), SKF525-A (a), sulfaphenazole (b), quinine (c) or troleandomycin (d), and their respective control rats (filled circles). Data are presented as mean±s.d.