LERCANIDIPINE-FLUVASTATIN INTERACTION: STEREOSELECTIVITY IN PHARMACOKINETICS - EXPERIMENTAL STUDY.

FF06

Boralli, VB; Cardoso, JLC; Graciani, FS; Farias, MT; Marques, MP; Coelho, EB; Lanchote, VL.

(1) Departamento de Análises Clínicas, Toxicológicas e Broamtológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto – USP, Av do Café, s/n  - Ribeirão Preto - SP - Brasil

(2) Departamento de Clínica Médica- Faculdade de Medicina de Ribeirão Preto – USP., Av dos Bandeirantes, 3900 - Ribeirão Preto - SP - Brasil

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 to their respective antipodes. The present study describes the enantioselective pharmacokinetic interaction between LER and FV in Wistar rats. Male Wistar rats (n = 6 per group) received racemic LER (3mg/kg) or FV (5mg/kg) or LER plus FV. Serial blood samples were collected from 0-24 h. Plasma concentrations of the LER and FV enantiomers were determined by LC-MS/MS and pharmacokinetic parameters were evaluated using the WinNonlin software. The Wilcoxon and Mann-Whitney tests (P < 0.05) 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 (281.6 vs 274.6 ng.h/mL) and for R-LER compared to S-LER (67.9 vs 18.9 ng.h/mL). The pharmacokinetic parameters of FV were not enantioselective when combined with LER (AUC: (-)-3S,5R-FV: 545.1; (+)-3R,5S-FV: 504.8 ng.h/mL). There was a significant reduction in S-LER (18.9 vs 13.3 ng.h/mL) AUC values when FV was co-administered. In conclusion, the interaction between FV-LER might be relevant since AUC values of (+)-3R,5S-FV were increased when LER was co-administered and AUC values of the S-LER, the eutomer, was  reduced when FV was co-administered.