title: Identification of the rat liver cytochrome P450 enzymes involved in the metabolism of the calcium channel blocker dipfluzine hydrochloride.
abstract: This study aimed to identify the specific cytochrome P450 (CYP450) enzymes involved in the metabolism of dipfluzine hydrochloride using the combination of a chemical inhibition study, a correlation analysis and a panel of recombinant rat CYP450 enzymes. The incubation of Dip with rat liver microsomes yielded four metabolites, which were identified by liquid chromatography-coupled tandem mass spectrometry (LC/MS/MS). The results from the assays involving eight selective inhibitors indicated that CYP3A and CYP2A1 contributed most to the metabolism of Dip, followed by CYP2C11, CYP2E1 and CYP1A2; however, CYP2B1, CYP2C6 and CYP2D1 did not contribute to the formation of the metabolites. The results of the correlation analysis and the assays involving the recombinant CYP450 enzymes further confirmed the above results and concluded that CYP3A2 contributed more than CYP3A1. The results will be valuable in understanding drug-drug interactions when Dip is coadministered with other drugs.
authors.affiliation: Department of Pharmacology, Hebei Medical University, Key Laboratory of Pharmacology and Toxicology for New Drug, Hebei Province, 361 East Zhongshan Road, Shijiazhuang 050017, China; School of Pharmacy, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang 050017, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: School of Pharmacy, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang 050017, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Shi
authors.affiliation: School of Pharmacy, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang 050017, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: School of Public Health, Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang 050017, China.
authors.forename: Weili
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Hebei Medical University, Key Laboratory of Pharmacology and Toxicology for New Drug, Hebei Province, 361 East Zhongshan Road, Shijiazhuang 050017, China. Electronic address: lyjunxia@gmail.com.
authors.forename: Junxia
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D002936:Cinnarizine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000302:isolation & purification; D003577:Cytochrome P-450 Enzyme System / Q000302:isolation & purification*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
chemical_list: D002121:Calcium Channel Blockers; D002936:Cinnarizine; C065758:dipfluzine; D003577:Cytochrome P-450 Enzyme System; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A
keywords: CYP450 enzymes; Dipfluzine hydrochloride; Metabolism; Rat liver microsomes