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.

Pharmacokinetic drug&ndash;drug interactions between 1,4-dihydropyridine calcium channel blockers and statins: factors determining interaction strength and relevant clinical risk management

“…Generally, the metabolic DDI potential between these two drugs is minimal. However, a randomized crossover, three-period clinical trial presented surprising findings 17. The study was conducted in healthy subjects treated with a single oral dose of racemic lercanidipine (20 mg) or fluvastatin (40 mg), or lercanidipine plus fluvastatin.…”

“…The AUC values of (+)-3R,5S-fluvastatin were increased, and the stereoselectivity in the fluvastatin pharmacokinetics was abolished after the addition of lercanidipine, whereas coadministered fluvastatin significantly decreased the AUC values of lercanidipine enantiomers (S-lercanidipine: 8.06 versus 13.90 ng·h/mL and R-lercanidipine: 6.76 versus 11.88 ng·h/mL). Boralli et al speculated that fluvastatin induced intestinal P-gp and consequently, that it reduces the bioavailability of lercanidipine 17. Fluvastatin pharmacokinetics are also dependent on ABCB1 (adenosine triphosphate [ATP]-binding cassette transporter subfamily B member 1) (the gene coding P-gp) polymorphism.…”

Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway

“…The absence of systematic and rigorous descriptions of metabolites and pharmaceutical compounds poses a significant challenge. Example 1, fluvastatin consists of two enantiomers, represented by PubChem compound identifiers (CIDs) 1548972 and 446155, with the 3R, 5S enantiomer (CID 446155) being significantly more pharmacologically active than the other (Di Pietro et al, ; Boralli et al, ). Commercial preparations used in vitro often vary in their stereochemical composition, with both enantiomers available individually, as well as in a racemic mixture.…”

Análise enantiosseletiva da lercanidipina: controle de qualidade de formulações farmacêuticas por eletroforese capilar e avaliação da fotodegradação por cromatografia líquida de alta eficiência

“…A LER exerce seu efeito por promover vasodilatação decorrente do bloqueio de canais de cálcio do tipo L nas membranas celulares do músculo liso vascular. A LER, em dose única diária, exerce efeito anti-hipertensivo de longa duração, é bem tolerada e apresenta poucos efeitos adversos (BORALLI et al, 2009).…”