title: Inhibitory effects of nicardipine to cytochrome P450 (CYP) in human liver microsomes.
abstract: To anticipate drug-drug interactions by nicardipine in vivo, cytochrome P450 (CYP) forms responsible for the metabolism of nicardipine and inhibition of CYP-dependent drug metabolism by nicardipine were investigated. Microsomes of human B-lymphoblastoid cells expressing each human CYP form were used for the metabolism of nicardipine. Inhibitory effects of nicardipine on drug metabolism were studied using human liver microsomes. CYP2C8, CYP2D6 and CYP3A4 were identified as major CYP forms for the metabolism of nicardipine in human liver microsomes. Nicardipine strongly inhibited two-pathways of triazolam hydroxylation both catalyzed by CYP3A4. Comparison of three Ca(2+) antagonists, nicardipine, nifedipine, and diltiazem revealed that only nicardipine showed such a strong inhibitory potency on the typical CYP2D6-catalyzed drug metabolism. Furthermore, nicardipine inhibited other reactions catalyzed by CYP1A, CYP2A6, CYP2C8, CYP2C9 and CYP2C19 with K(i) values ranging from 1.1 to 29.4 microM. In conclusion, nicardipine was a relatively potent inhibitor of human CYP2D6, CYP3A4 and CYP2C (especially for CYP2C8 and CYP2C19) in vitro, suggesting that drug-drug interactions between nicardipine and other drugs metabolized mainly by these CYP forms appear to occur in vivo.
authors.affiliation: Laboratory of Drug Metabolism, Hokkaido University Graduate School of Pharmaceutical Sciences, Sapporo 060-0812, Japan. nkatsu@showa.gunma-u.ac.jp
authors.forename: Katsunori
authors.initials: K
authors.lastname: Nakamura
authors.forename: Noritaka
authors.initials: N
authors.lastname: Ariyoshi
authors.forename: Takafumi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fukunaga
authors.forename: Saburou
authors.initials: S
authors.lastname: Higuchi
authors.forename: Kunio
authors.initials: K
authors.lastname: Itoh
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagashima
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
authors.forename: Koujirou
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Ryuya
authors.initials: R
authors.lastname: Horiuchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kamataki
mesh_terms: D002460:Cell Line; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology*; D009529:Nicardipine / Q000494:pharmacology*
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D009529:Nicardipine