Role of human cytochrome P450 3A4 in the metabolism of DA-8159, a new erectogenic.
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.
Ji
H Y
HY
Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy and Phytofermentation Research Center, Wonkwang University, Iksan 570-749, Korea.
Lee
H W
HW
Kim
H H
HH
Kim
D S
DS
Yoo
M
M
Kim
W B
WB
Lee
H S
HS
D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D007172:Erectile Dysfunction / Q000188:drug therapy; D006801:Humans; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D025941:Protein Interaction Mapping / Q000379:methods*; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism* / Q000627:therapeutic use; D013449:Sulfonamides; D000096926:Benzenesulfonamides
D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C502127:DA-8164; C104464:CYP3A protein, human; C510163:CYP3A4 protein, human; C419664:udenafil; D000096926:Benzenesulfonamides