Evaluation of the inhibitory and induction potential of YM758, a novel If channel inhibitor, for human P450-mediated metabolism.
This study was designed to examine the in vitro metabolism of YM758, a novel cardiovascular agent, and to evaluate its potential to cause drug interactions and induction of CYP isozymes. After incubation with pooled human liver microsomes, YM758 was converted to two major metabolites (AS2036313-00, and YM-394111 or YM-394112). The formation of AS2036313-00, and YM-394111 or YM-394112 were mediated by CYP2D6 and CYP3A4, respectively, which was elucidated by using a bank of human liver microsomes and recombinant CYP enzymes in combination with the utilization of typical substrates and inhibitors. The Ki values of YM758 for midazolam, nifedipine, and metoprolol metabolism ranged from 59 to 340 microM, being much higher than the YM758 concentration in human plasma. The formation of AS2036313-00, and YM-394111 or YM-394112 was inhibited by quinidine and ketoconazole with Ki values of 140 and 0.24 microM, respectively, which indicates that YM758 metabolism may be affected by coadministration of strong CYP2D6 and 3A4 inhibitors in vivo, given the clinical plasma concentrations of quinidine and ketoconazole. After human hepatocytes were exposed to 10 microM YM758, microsomal activity and mRNA level for CYP1A2 were not induced while those for CYP3A4 were slightly induced. The tested concentration was much higher than that in human plasma, which suggests that the induction potential of YM758 is also negligible.
Umehara
K I
KI
Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan.
Susaki
Y
Y
Van Teylingen
R H J
RH
Neat
J N
JN
Ndikum-Moffor
F
F
Noguchi
K
K
Usui
T
T
Parkinson
A
A
Kamimura
H
H
D001549:Benzamides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D008875:Middle Aged; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism
D001549:Benzamides; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D012333:RNA, Messenger; C530155:YM 758; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human