Influence of ethylbenzene on the pharmacokinetic enantiosselective of lercanidipine in rats. / Influência do etilbenzeno na farmacocinética enantiosseletiva do lercanidipino em ratos

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

Cytochrome P450 (CYP) is responsible for biotransformation of drugs, pollutants and other xenobiotics. Lercanidipine (LER), clinically employed as quiral compound in the treatment of arterial hypertension, is biotransformed by CYP3A4. Etylbenzene (EBZ), a solvent of large industrial use, is substrate and inducer of CYP3A in rats. The present study investigated influence of EBZ in pharmacokinetics of racemic LER 3 mg kg-1 in rats. Animals were divided into 3 groups: control, exposed to EBZ 436 mg/m3 and exposed to EBZ 876 mg/m3. Animals were exposed to EBZ during 6 hours, in a chamber of exposition with nose only exposure system, 5 consecutive days. Serial blood samples (n=6, each time of collection) were collected up to 6 hours after LER administration. LER enantiomers were separated on a quiral phase column and analyzed by LC-MS/MS. LER pharmacokinetics was enantiosselective in control rats not treated with EBZ, with plasma accumulation of (-)-(R)-LER distomer (AUC0-? = 19.23 vs 5.53 Ig min-1 mL-1) and enantiomeric ratios of (-)-(R)/(+)-(S)-LER of 3.87. Apparent clearance (78.25 vs 277.08 mL min-1 kg-1) and apparent volume of distribution (16.63 vs 48.95 L kg-1) were decreased for (-)-(R)-LER distomer. Kinetic disposition of LER for animals exposed to EBZ 436 and 876 mg/m3, as for control group, was enantiosselective with plasma accumulation of (-)-(R)-LER enantiomer. Plasmatic accumulation of (-)-(R)-LER enantiomer for 436 mg/m3 and 876 EBZ mg/m3 groups (34.06 vs 10.23 Ig min mL-1 and 23.79 vs 6.97 Ig min mL-1, respectively) was consequent of lower volume of distribution (17.02 vs 57.79 L kg-1 and 23.11 vs 76.05 L kg-1) and lower apparent clearance (44.87 vs 147.60 mL min-1 kg-1 and 65.57 vs 258.21 mL min-1 kg-1). No differences were observed in AUC(-)/(+) ratios between the control group (3.87), 436 EBZ mg/m3 (3,35) and EBZ 876 mg/m3 (4.26). Pharmacokinetic parameters of LER enantiomers did not show significant differences between animals of control group and exposed animals to EBZ 434 and 868 mg/m3.

ASSUNTO(S)

etilbenzeno eethylbenzene pharmacokinetics. lercanidipine enantiômeros enantiomers farmacocinética lercanidipino

ACESSO AO ARTIGO

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