Dose-dependent pharmacokinetic interaction between antipyrine and paracetamol in vivo and in vitro when administered as a cocktail in pig

Abstract

1. The pharmacokinetic interactions between paracetamol (PA) and antipyrine (AP) were studied in pigs in order to investigate the usefulness of this combination for the simultaneous assessment of oxidative and conjugative metabolism.

2. When both drugs were given at a dose of 5 mg/kg, AP plasma clearance was reduced from 2.22 to 0.96 lh⁻¹ kg⁻¹. PA clearance was not changed in comparison with control values.

3. At a dose of 2 mg/kg no pharmacokinetic interaction between the two drugs was observed.

4. The only oxidative AP metabolite found in urine was 4-hydroxyantipyrine (4-OHA). It accounted for 80% of the dose and, like PA, it was completely glucuronidated.

5. The glucuronidation of PA has been studied in vitro in pig liver microsomes. The apparent K_m value for PA glucuronidation was 40 mM with a V_max = 54 nmol min⁻¹ mg protein⁻¹. To determine if 4-OHA and PA competed for the same UDP-glucuronosyl-transferase, the effect of 4-OHA and AP on PA glucuronidation was studied. It appeared that 4-OHA was a competitive inhibitor with a K_{i app} = 0.07 μM, whereas AP had no effect.

5. Results suggest a dose-dependent interaction between AP and PA, which may be due to competition at the level of glucuronidation. Therefore, the usefulness of AP and PA in vivo in a cocktail for metabolism studies is limited.