RT Journal Article
SR Electronic
T1 IN VITRO METABOLISM OF THE CALMODULIN ANTAGONIST DY-9760e (3-[2-[4-(3-CHLORO-2-METHYLPHENYL)-1-PIPERAZINYL]ETHYL]-5,6-DIMETHOXY-1-(4-IMIDAZOLYLMETHYL)-1<em>H</em>-INDAZOLE DIHYDROCHLORIDE 3.5 HYDRATE) BY HUMAN LIVER MICROSOMES: INVOLVEMENT OF CYTOCHROMES P450 IN ATYPICAL KINETICS AND POTENTIAL DRUG INTERACTIONS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1628
OP 1636
DO 10.1124/dmd.105.004903
VO 33
IS 11
A1 Shuko Tachibana
A1 Yuko Fujimaki
A1 Hiroyuki Yokoyama
A1 Osamu Okazaki
A1 Ken-ichi Sudo
YR 2005
UL http://dmd.aspetjournals.org/content/33/11/1628.abstract
AB Human cytochrome P450 (P450) isozyme(s) responsible for metabolism of the calmodulin antagonist 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e) and kinetic profiles for formation of its six primary metabolites [M3, M5, M6, M7, M8, and DY-9836 (3-[2-[4-(3-chloro-2-methylphenyl)piperazinyl]ethyl]-5,6-dimethoxyindazole)] were identified using human liver microsomes and recombinant P450 enzymes. In vitro experiments, including an immunoinhibition study, correlation analysis, and reactions with recombinant P450 enzymes, revealed that CYP3A4 is the primary P450 isozyme responsible for the formation of the DY-9760e metabolites, except for M5, which is metabolized by CYP2C9. Additionally, at clinically relevant concentrations, CYP2C8 and 2C19 make some contribution to the formation of M3 and M5, respectively. The formation rates of DY-9760e metabolites except for M8 by human liver microsomes are not consistent with a Michaelis-Menten kinetics model, but are better described by a substrate inhibition model. In contrast, the enzyme kinetics for all metabolites formed by recombinant CYP3A4 can be described by an autoactivation model or a mixed model of autoactivation and biphasic kinetics. Inhibition of human P450 enzymes by DY-9760e in human liver microsomes was also investigated. DY-9760e is a very potent competitive inhibitor of CYP2C8, 2C9 and 2D6 (Ki 0.25–1.7 μM), a mixed competitive and noncompetitive inhibitor of CYP2C19 (Ki 2.4 μM), and a moderate inhibitor of CYP1A2 and 3A4 (Ki 11.4–20.1 μM), suggesting a high possibility for human drug-drug interaction. The American Society for Pharmacology and Experimental Therapeutics