title: Influence of N-hexane inhalation on the enantioselective pharmacokinetics and metabolism of verapamil in rats.
abstract: Verapamil (VER) is commercialized as a racemic mixture of the (+)-(R)-VER and (-)-(S)-VER enantiomers. VER is biotransformed into norverapamil (NOR) and other metabolites through CYP-dependent pathways. N-hexane is a solvent that can alter the metabolism of CYP-dependent drugs. The present study investigated the influence of n-hexane (nose-only inhalation exposure chamber at concentrations of 88, 176, and 352 mg/m3) on the kinetic disposition of the (+)-(R)-VER, (-)-(S)-VER, (R)-NOR and (S)-NOR in rats treated with a single dose of racemic VER (10 mg/kg). VER and NOR enantiomers in rat plasma was analyzed by LC-MS/MS (m/z = 441.3 > 165.5 for the NOR and m/z 455.3 > 165.5 for the VER enantiomers) using a Chiralpak AD column. Pharmacokinetic analysis was performed using a monocompartmental model. The pharmacokinetics of VER was enantioselective in control rats, with higher plasma proportions of the (-)-(S)-VER eutomer (AUC(0-infinity) = 250.8 vs. 120.4 ng/ml/h; P < or = 0.05, Wilcoxon test). The (S)-NOR metabolite was also found to accumulate in plasma of control animals, with an S/R AUC(0-infinity) ratio of 1.5. The pharmacokinetic parameters AUC(0-infinity), Cl/F, Vd/F, and t(1/2) obtained for VER and NOR enantiomers were not altered by nose-only exposure to n-hexane at concentrations of 88, 176, or 352 mg/m3 (P > 0.05, Kruskal-Wallis test). However, the verapamil kinetic disposition was not enantioselective for the animals exposed to n-hexane at concentrations equal to or higher than the TLV-TWA. This finding is relevant considering that the (-)-(S)-VER eutomer is 10-20 times more potent than R-(+)-VER in terms of its chronotropic effect on atrioventricular conduction in rats and humans.
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Fabiano H
authors.initials: FH
authors.lastname: Mateus
authors.forename: José S
authors.initials: JS
authors.lastname: Lepera
authors.forename: Maria Paula
authors.initials: MP
authors.lastname: Marques
authors.forename: Vanessa B
authors.initials: VB
authors.lastname: Boralli
authors.forename: Vera L
authors.initials: VL
authors.lastname: Lanchote
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D019540:Area Under Curve; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006586:Hexanes / Q000008:administration & dosage*; D051381:Rats; D013237:Stereoisomerism; D014700:Verapamil / Q000493:pharmacokinetics*
chemical_list: D002121:Calcium Channel Blockers; D006586:Hexanes; C026385:n-hexane; D014700:Verapamil