Vol.55 No.S-1 October 2007
In vitro metabolism and the effect on human cytochrome P450s of garenoxacin
Research Laboratories, Toyama Chemical Co., Ltd., 2-4-1 Shimookui, Toyama, Japan
Abstract
To assess the possibility of pharmacokinetic drug-drug interactions of garenoxacin mesilate hydrate(GRNX), we investigated the metabolism of GRNX in human liver microsomes, the induction effect of GRNX on cytochrome P450(CYP) 1A2 and CYP3A4 activity in primary cultured human hepatocytes, and the inhibition effect of GRNX on the metabolic activity of probe substrates for CYP isoforms in human liver microsomes. GRNX was hardly metabolized by human liver microsomes in the presence or absence of NADPH, showing that CYPs are unlikely to be involved in the metabolism of GRNX. GRNX did not exhibit the induction effect on CYP1A2 and CYP3A4 activity at up to 100 μmol/L, which was approximately 17-fold higher than the unbound GRNX concentration in plasma (approximately 6 μmol/L, calculated from the Cmax at 400 mg repeated oral dose in humans). GRNX had little inhibition effect on the CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 activity, and the 50% inhibition concentration for these CYP isoforms exceeded 1,000 μmol/L. In conclusion, GRNX is unlikely to cause CYP-mediated drug-drug interactions in humans when it is administered concomitantly with other drugs.
Key word
garenoxacin, cytochrome P450, drug-drug interaction
Received
April 27, 2007
Accepted
August 9, 2007
Jpn. J. Chemother. 55 (S-1): 87-94, 2007
