A simplified approach for evaluation of hepatic drugoxidizing activity with a simultaneous determination of caffeine and trimethadione and their demethylated metabolites in rats with a selective cytochrome P‐450 inducer

摘要

AbstractWe determined the blood concentrations of caffeine (CA) and its three primary dimethylxanthine metabolites: theobromine (TB), paraxanthine (PX), and theophylline (TP), and trimethadione (TMO) and its demethylated metabolite dimethadione (DMO) after the simultaneous administration of CA (10 mg kg−1) and TMO (4 mg kg−1) to rats pretreated with phenobarbital (PB: 40 and 80 mg kg−1i.p. daily for 3 days) and 3‐methylcholanthrene (MC: 10 and 20 mg kg−1i.p. daily for 2 days). After the oral administration of CA and TMO, the PB‐pretreated rats showed a significant increase in TMO metabolism, whereas the CA metabolism was greatly accelerated in rats pretreated with MC.In five pretreated groups, there were correlations which were determined 1 h after the administration of CA and TMO, between the plasma half‐life (t1/2) of CA and the TB/CA, PX/CA, and TP/CA ratios. The coefficients of correlation (r) ranged from −0·881 to −0·908, and the coefficients of correlation between the CL of CA and the TB/CA, PX/CA, and TP/CA ratios ranged from 0·959 to 0·989.There were high correlations between thet1/2of TMO and the DMO/TMO ratio at 1 h after administration withr= −0·966, and between the CL of TMO and the DMO/TMO ratio withr= 0·971.The above results suggest that one blood sampling after the simultaneous administration of CA and TMO enables prediction of the degree of each hepatic drug‐oxidizing activity because the P‐450 isozymes involved in metabolis