Role of human cytochrome P450 3A4 in the metabolism of DA-8159, a new erectogenic.

H Y Ji, H W Lee, H H Kim, D S Kim, M Yoo, W B Kim, H S Lee

Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy and Phytofermentation Research Center, Wonkwang University, Iksan 570-749, Korea.

Xenobiotica; the fate of foreign compounds in biological systems 2004 Nov-Dec

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The purpose of this paper was to characterize cytochrome P450 (CYP) enzymes involved in N-dealkylation of a new oral erectogenic, DA-8159 to DA-8164, a major circulating active metabolite, in human liver microsomes and to investigate the inhibitory potential of DA-8159 on CYP enzymes. CYP3A4 was identified as the major enzyme responsible for DA-8159 N-dealkylation to DA-8164 based on correlation analysis and specific CYP inhibitor and antibody-mediated inhibition study in human liver microsomes, and DA-8159 metabolism in cDNA expressed CYP enzymes. There is the possibility of drug-drug interactions when prescribing DA-8159 concomitantly with known inhibitors or inducers of CYP3A4. DA-8159 was found to be only a very weak inhibitor of eight major CYPs (1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4), the largest inhibition occurring against CYP2D6 (IC5o 67.7 microM) in human liver microsomes. Drug-drug interactions would not be predicted on the basis of DA-8159 inhibiting the metabolism of coadministered drugs.

Citation

H Y Ji, H W Lee, H H Kim, D S Kim, M Yoo, W B Kim, H S Lee. Role of human cytochrome P450 3A4 in the metabolism of DA-8159, a new erectogenic. Xenobiotica; the fate of foreign compounds in biological systems. 2004 Nov-Dec;34(11-12):973-82