TY - JOUR
T1 - Effects of enzyme inducers and inhibitors on the pharmacokinetics of metformin in rats
T2 - Involvement of CYP2C11, 2D1 and 3A1/2 for the metabolism of metformin
AU - Choi, Y. H.
AU - Lee, M. G.
PY - 2006/10/11
Y1 - 2006/10/11
N2 - 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 (CL NR) of metformin was compared with that of controls. Key results: In rats pretreated with dexamethasone, the CL NR was significantly faster (57% increase) than for the controls. In rats pretreated with SKF-525-A, sulfaphenazole, quinine, and troleandomycin, the CL NR was significantly slower (24.3, 62.9, 77.6, and 78.7% decrease, respectively) than for the controls. However, the CL NR 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.
AB - 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 (CL NR) of metformin was compared with that of controls. Key results: In rats pretreated with dexamethasone, the CL NR was significantly faster (57% increase) than for the controls. In rats pretreated with SKF-525-A, sulfaphenazole, quinine, and troleandomycin, the CL NR was significantly slower (24.3, 62.9, 77.6, and 78.7% decrease, respectively) than for the controls. However, the CL NR 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.
KW - 2D1 and 3A1/2
KW - CYP inducers and inhibitors
KW - CYP2C11
KW - Metformin
KW - Pharmacokinetics
KW - Rats
UR - http://www.scopus.com/inward/record.url?scp=33750043803&partnerID=8YFLogxK
U2 - 10.1038/sj.bjp.0706875
DO - 10.1038/sj.bjp.0706875
M3 - Article
C2 - 16940989
AN - SCOPUS:33750043803
SN - 0007-1188
VL - 149
SP - 424
EP - 430
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 4
ER -