Nifedipine Does Not Alter the Pharmacokinetics of Venlafaxine Enantiomers in Healthy Subjects Phenotyped for CYP2D6, CYP2C19, and CYP3A

• Published in: Journal of clinical pharmacology Vol. 61; no. 3; p. 319
• Main Authors: Tozatto, Eduardo, Benzi, Jhohann Richard de Lima, Rocha, Adriana, Coelho, Eduardo Barbosa, Lanchote, Vera Lucia
• Format: Journal Article
• Language: English
• Published: England 01.03.2021
• Subjects: Administration, Oral; Adult; Antidepressive Agents, Second-Generation - pharmacokinetics; Area Under Curve; Chromatography, Liquid; Cross-Over Studies; Cyclohexanols - blood; Cytochrome P-450 CYP2C19 - metabolism; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP3A - metabolism; Desvenlafaxine Succinate - blood; Drug Interactions; Humans; Male; Nifedipine - pharmacology; Phenotype; Stereoisomerism; Tandem Mass Spectrometry; Venlafaxine Hydrochloride - pharmacokinetics; Young Adult; pharmacokinetics; nifedipine; enantiomers; metabolism; P-gp; venlafaxine
• ISSN: 1552-4604
• DOI: 10.1002/jcph.1745

Venlafaxine (VEN) is a P-glycoprotein (P-gp) substrate, and nifedipine has been described by in vitro and experimental studies as a P-gp inhibitor. The present study aimed to investigate whether nifedipine alters the kinetic disposition of VEN enantiomers and their metabolites in healthy subjects. A crossover study was conducted in 10 healthy subjects phenotyped as extensive metabolizers for cytochrome P450 (CYP) 2D6, CYP2C19, and CYP3A. In phase 1, the subjects received a single oral dose of 150 mg racemic VEN, and in phase 2, a single oral dose of 40 mg nifedipine was administered with the VEN treatment. Plasma concentrations of VEN enantiomers and their metabolites O-desmethylvenlafaxine and N, O- didesmethylvenlafaxine (ODV and DDV, respectively) were evaluated by liquid chromatography with tandem mass spectrometry up to 72 hours after drug administration. Phase 2 was compared with phase 1 using the 90% confidence interval (CI) of the ratio of geometric means for C and area under the curve (AUC). AUC enantiomeric ratios S-(+)/R-(-) were evaluated within each and between phases using the Wilcoxon test (P ≤ .05). The kinetic disposition of VEN was enantioselective (phase 1) with VEN S-(+)/R-(-) AUC ratio median of 2.83 (AUC , 526 vs 195 ng·h/mL). However, AUC median did not differ between enantiomers for the metabolites ODV (1971 vs 2226 ng·h/mL) and DDV (199 vs 151 ng·h/mL). The 90%CI of the ratio of geometric means showed that the phases are bioequivalent. A single oral dose of 40 mg nifedipine did not alter VEN enantiomer pharmacokinetics in healthy subjects.