title: Enantioselectivity in the pharmacokinetic interaction between fluvastatin and lercanidipine in healthy volunteers.
abstract: Hypertension and dyslipidemia are independent risk factors for cardiovascular mortality and are frequently present in the same patient. Fluvastatin (FV), used to reduce cholesterol levels, and lercanidipine (LER), used to control blood pressure, are marketed as racemic mixtures. Therapeutic activities are 30-fold higher for (+)-3R, 5S-FV and 100- to 200-fold higher for S-LER compared with their respective antipodes. The present study describes the enantioselective pharmacokinetic interaction between LER and FV in healthy volunteers. A crossover randomized study was conducted in 3 phases on 8 volunteers treated with a single oral racemic dose of LER (20 mg) or FV (40 mg) or LER plus FV. Serial blood samples were collected from 0 to 24 hours. Plasma concentrations of the LER and FV enantiomers were determined by liquid chromatography/tandem mass spectrometry, and pharmacokinetic parameters were evaluated using the WinNonlin software. The Wilcoxon and Mann-Whitney tests (P < .05) were used to analyze enantiomer ratios and the pharmacokinetic drug interaction. Data are expressed as medians. In monotherapy, the kinetic disposition of both FV and LER was enantioselective. AUC values were significantly higher for (-)-3S,5R-FV than for (+)-3R,5S-FV (358.20 vs 279.68 ng.h/mL) and for S-LER compared with R-LER (13.90 vs 11.88 ng.h/mL). The pharmacokinetic parameters of FV were not enantioselective when combined with LER (AUC: (-)-3S,5R-FV: 325.21; (+)-3R,5S-FV: 316.44 ng.h/mL). There was a significant reduction in S-LER (8.06 vs 13.90 ng.h/mL) and R-LER (6.76 vs 11.88 ng.h/mL) AUC values when FV was coadministered. In conclusion, the interaction between FV-LER might be clinically relevant because AUC values of (+)-3R,5S-FV were increased when LER was coadministered, and AUC values of the 2 LER enantiomers were reduced when FV was coadministered.
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Departamento de Análises Clínicas, Toxicológicas and Bromatológicas, Avenida do Café s.n. Campus da USP, 14040-903, Ribeirão Preto, SP, Brazil.
authors.forename: Vanessa Bergamin
authors.initials: VB
authors.lastname: Boralli
authors.forename: Eduardo Barbosa
authors.initials: EB
authors.lastname: Coelho
authors.forename: Stefânia Amaral
authors.initials: SA
authors.lastname: Sampaio
authors.forename: Maria Paula
authors.initials: MP
authors.lastname: Marques
authors.forename: Vera Lucia
authors.initials: VL
authors.lastname: Lanchote
mesh_terms: D000328:Adult; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics* / Q000494:pharmacology; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004095:Dihydropyridines / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D005229:Fatty Acids, Monounsaturated / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D018709:Statistics, Nonparametric; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D000924:Anticholesteremic Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D000077340:Fluvastatin; C060343:lercanidipine