RESUMO
OBJECTIVE: The objective of our study was to evaluate in humans the drug-drug interaction occurring during the concomitant administration of cisapride and simvastatin, two well-known substrates of CYP3A4. METHODS: Eleven healthy men aged between 20 years and 35 years gave their written informed consent to participate in the study. Each participant received repeated doses of cisapride and/or simvastatin. At first, subjects received cisapride alone, 10 mg every 8 h, for 3 days. Then, the drug was given at the same regimen during concomitant administration of simvastatin, 20 mg every 12 h for 4 days, starting on the night of day 3. Finally, cisapride was stopped and subjects received simvastatin (20 mg every 12 h) for four additional days. RESULTS: Simvastatin administration caused a 14 +/- 20% increase in the AUC0-8 of cisapride. In contrast, plasma concentrations of simvastatin were unaltered by the coadministration of cisapride, whereas plasma concentrations of simvastatin acid, its active metabolite, were decreased by 33 +/- 24%. CONCLUSION: The concomitant administration of the prokinetic agent cisapride and the 3-hydroxy-3-methylgluaryl CoA reductase inhibitor simvastatin resulted in altered pharmacokinetics of both drugs. Increased plasma concentrations of cisapride suggest that some patients may be at risk of toxicity while receiving both drugs, whereas the decrease in simvastatin acid plasma concentrations suggests that cholesterol lowering effects of simvastatin treatment may be blunted.