In vitro metabolism of a novel PPARγ agonist, KR-62980, and its stereoisomer, KR-63198, in human liver microsomes and by recombinant cytochrome P450s

Abstract

1. KR-62980 and its stereoisomer KR-63198 are novel and selective peroxisome proliferator-activated receptor gamma (PPARγ) modulators with activity profiles different from that of rosiglitazone. This study was performed to identify the major metabolic pathways for KR-62980 and KR-63198 in human liver microsomes.

2. Human liver microsomal incubation of KR-62980 and KR-63198 in the presence of a β-nicotinamide adenine dinucleotide phosphate (NADPH)-generating system resulted in hydroxy metabolite formation. In addition, the specific cytochrome P450s (CYPs) responsible for KR-62980 and KR-63198 hydroxylation were identified by using a combination of chemical inhibition in human liver microsomes and metabolism by recombinant P450s. It is shown that CYP1A2, CYP2D6, CYP3A4, and CYP3A5 are the predominant enzymes in the hydroxylation of KR-62980 and KR-63198.

3. The intrinsic clearance through hydroxylation was consistently and significantly higher for KR-62980 than for KR-63198, indicating metabolic stereoselectivity (CL_int of 0.012 ± 0.001 versus 0.004 ± 0.001 μl min⁻¹ pmol⁻¹ P450, respectively).

4. In a drug–drug interaction study, KR-62980 and KR-63198 had no effect on the activities of the P450s tested (IC₅₀ > 50 μM), suggesting that in clinical interactions between KR-62980 and KR-63198 the P450s tested would not be expected.

Keywords::

• KR-62980
• KR-63198
• metabolism
• microsomes
• liquid chromatography/tandem mass spectrometry (LC/MS/MS)
• CYP1A2
• CYP2D6
• CYP3A4
• CYP3A5

Acknowledgements

This work was supported by a grant (No. CBM32-B4000-01-01-00) from the Center for Biological Modulators of the 21st Century Frontier R&D Program, Ministry of Science and Technology, Korea, and the Korea Health 21 R&D Project, Ministry of Health and Welfare, R. O. K. (AO30001).