Ranitidine Increases Bioavailability of Acetaminophen by Inhibiting First‐Pass Glucuronidation in Man

The effect of the histamine H2 receptor antagonist, ranitidine, on plasma concentrations of acetaminophen was investigated with respect to hepatic metabolism, in five volunteers. Acetaminophen (1000 mg) together with ranitidine (300 mg), placebo or at 1 h after ranitidine (300 mg) was orally administered to five healthy male volunteers. Venous blood samples were taken before and after drug administration. Plasma acetaminophen and acetaminophen conjugates (glucuronide and sulphate) were determined by HPLC. The pharmacokinetic parameters were calculated from the plasma acetaminophen concentration-time curves from each volunteer. The area under the plasma acetaminophen concentration-time curve from 0 to 3 h (AUC0–3) significantly (P < 0.01) increased from 13.03 ± 0.84 μg h mL−1 (placebo coadministration) to 21.30 ± 0.60 μg h mL−1 (ranitidine coadministration). The peak plasma acetaminophen concentration significantly (P < 0.01) increased from 18.30 ± 2.26 μg mL−1 (placebo coadministration) to 34.14 ± 1.07 μg mL−1 (ranitidine coadministration) 30 min after administration. Plasma acetaminophen concentrations with ranitidine were significantly increased at 15 to 120 min compared with placebo. Plasma acetaminophen glucuronide conjugate concentrations with ranitidine were significantly decreased at 15 to 45 min compared with placebo, whereas plasma acetaminophen sulphate conjugate concentrations were not significantly altered. Plasma acetaminophen and acetaminophen conjugate concentrations were not significantly different between placebo-coadministration and in the case where acetaminophen was orally administered 1 h after ranitidine. Coadministration of acetaminophen and ranitidine reduced plasma acetaminophen glucuronide concentrations and significantly increased plasma acetaminophen concentrations. The effects of ranitidine are as a result of the prevention of first-pass hepatic metabolism, by prevention of acetaminophen glucuronyltransferase. Thus care must be taken when acetaminophen and ranitidine are coadministered.