Cisapride raises the bioavailability of paracetamol by inhibiting its glucuronidation in man

Abstract

Abstract The effect of cisapride on plasma concentrations of paracetamol was investigated with respect to hepatic metabolism. Paracetamol (1 g) together with cisapride (7.5 mg) or placebo was orally administered to five healthy male volunteers. Venous blood samples were taken before and after administration. Plasma paracetamol and its glucuronide and sulfate conjugates were measured by HPLC. The pharmacokinetic variables were calculated from the plasma concentration-time curves of each volunteer. The area under the plasma paracetamol concentration-time curve from 0 to 180 min (mean ± s.d.) increased from 1875.0 ± 112.8 μg min mL−1 (placebo coadministration) to 2238.8 ± 125.8 μg min mL−1 (cisapride coadministration) (P < 0.01). The mean maximum plasma paracetamol concentration (18.2 μg mL−1) with placebo was reached 30 min after administration, whereas mean maximum plasma paracetamol concentration (21.2 μg mL−1) with cisapride occurred 45 min after administration. The plasma paracetamol concentrations with cisapride were significantly greater at 45 to 120 min after administration compared with placebo. Plasma paracetamol glucuronide conjugate concentrations with cisapride were decreased at 15 to 60 min compared with placebo (P < 0.05), whereas plasma paracetamol sulfate conjugate concentrations did not change significantly. Hence the coadministration of paracetamol with cisapride reduced plasma paracetamol glucuronide concentrations and increased plasma paracetamol concentrations, presumably due to inhibition of paracetamol metabolism via paracetamol glucuronyltransferase. Thus, care is necessary when paracetamol and cisapride are coadministered.