Comparison of Hepatic Drug‐Oxidizing Activity after Simultaneous Administration of Two Probe Drugs, Caffeine and Trimethadione, to Human Subjects

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Abstract
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.

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