title: Concentration dependent stereoselectivity of propafenone N-depropylation metabolism with human hepatic recombinant CYP1A2.
abstract: Concentration dependency of stereoselective N-depropylation metabolism of propafenone was studied by using transgenic cell line expressing human CYP1A2. Enantiomers of propafenone and N-depropylpropafenone were separated and assayed simultaneously by RP-HPLC with precolumn GITC chiral derivatization. The experimental results showed that CYP1A2 was involved in enantioselective N-depropylation of propafenone and that the metabolic stereoselectivity depends on substrate concentration. For racemic propafenone, stereoselectivity was observed at low substrate concentration and was not seen at high substrate concentration. For individual isomers, S-(+)-propafenone was metabolized faster than its antipode at higher enantiomer concentrations and R-(-)-propafenone was eliminated faster than its antipode at lower enantiomer concentrations. There is interaction between S- and R-propafenone. R-(-)-propafenone inhibited the metabolism of S-(+)-propafenone with IC50 0.225 mmol/L for human CYP1A2.
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, The Second Hospital Affiliated to College of Medicinal Sciences, Zhejiang University, Hangzhou, Zhejiang P.R. China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhou
authors.forename: T W
authors.initials: TW
authors.lastname: Yao
authors.forename: Y N
authors.initials: YN
authors.lastname: Yu
authors.forename: S
authors.initials: S
authors.lastname: Zeng
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000201:enzymology*; D011405:Propafenone / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000889:Anti-Arrhythmia Agents; D011994:Recombinant Proteins; D011405:Propafenone; D019388:Cytochrome P-450 CYP1A2