Effect of cigarette smoking on caffeine and trimethadione N-demethylation catalyzed by different cytochrome P450 isozymes in patients with cirrhosis

It has been reported that caffeine (CA) metabolism in humans is catalyzed by cytochrome P450(CYP)1A2. Recently, we reported that human CYP3A4 and 2C, but not 1A2, contribute to trimethadione (TMO) N-demethylation in the human liver. In this study we simultaneously administered two indicators, CA (2 mg/kg) and TMO (4 mg/kg), which have different patterns of metabolism, to patients with cholelithiasis (control) or cirrhosis. The serum levels of CA and TMO, and their individual metabolites, were determined by high-performance liquid chromatography and gas chromatography, respectively. The metabolism of CA and TMO was significantly inhibited in patients with cirrhosis as compared with controls. The ratios of serum paraxanthine (PX)/CA and DMO/TMO at 4 h after administration of the two probe drugs were also significantly decreased in patients with cirrhosis. The PX/CA ratios of the smoking patients with cirrhosis were higher than those of non-smokers. No differences in serum DMO/TMO ratios were observed between the smokers and non-smokers. These results suggest that different estimations of hepatic oxidizing capacity, catalysed mainly by CYP2C and 3A4, are possible in humans.