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.
Tanaka
E
E
Institute of Community Medicine, University of Tsukuba, Ibaraki-ken, Japan.
Ishikawa
A
A
Yamamoto
Y
Y
Osada
A
A
Tsuji
K
K
Fukao
K
K
Iwasaki
Y
Y
D000328:Adult; D002110:Caffeine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004338:Drug Combinations; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000378:metabolism; D013805:Theobromine / Q000008:administration & dosage; D013806:Theophylline / Q000008:administration & dosage; D014293:Trimethadione / Q000008:administration & dosage / Q000493:pharmacokinetics*
D004338:Drug Combinations; D002110:Caffeine; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D010105:Oxygenases; D013805:Theobromine; C021183:1,7-dimethylxanthine; D014293:Trimethadione