Comparison of hepatic drug-oxidizing activity after simultaneous administration of two probe drugs, caffeine and trimethadione, to human subjects.

Pharmacokinetic interactions between caffeine 2 mg/kg and trimethadione 4 mg/kg were evaluated in 10 healthy volunteers. Whether administered alone or together, the total body clearance (CL), the apparent volume of distribution (Vd) and half-life (t1/2) of caffeine and trimethadione were the same, however, there was a weak correlation between the CL of caffeine and trimethadione [alone: r = 0.51 (P < 0.05); coadministered: r = 0.56 (P < 0.05)]. There were also weak correlations between the CL of trimethadione and the area under the serum concentration-time curves (AUC) of theobromine (r = -0.61, P < 0.05), paraxanthine (r = -0.69, P < 0.05) and theophylline (r = -0.60, P < 0.05), when the two drugs were administered alone. After combined administration, the correlation between the CL of trimethadione and the AUCs of the metabolites of caffeine were as follows: theobromine r = -0.63 (P < 0.05); paraxanthine r = -0.68 (P < 0.05); theophylline r = -0.65 (P < 0.05). These findings suggest that caffeine and trimethadione metabolism in healthy subjects is mediated by only in part by a form(s) of P450 enzymes involved.