Biol. Pharm. Bull. 28(6) 1071—1074 (2005)

variations in cytochrome P450 (CYP)-catalyzed drug metabolism, and that these variations sometimes lead to different susceptibilities of humans to the pharmacological and toxicological actions of drugs, toxic chemicals, and carcinogens. For example, there are large interindividual differences in the expression levels and catalytic activities of CYP enzymes in human liver. Additionally, multiple isozymes of carboxylesterases exist in humans, and interindividual variations of the carboxylesterase activities have important clinical implications. Recently, we have reported interindividual variations in the 2-hydroxylation (CYP3A4), sulfation, and glucuronidation of ethynylestradiol in human microsomes and cytosol. On the other hand, intrinsic metabolic clearance (CLint) is calculated as a ratio of Vmax to Km in order to predict in vivo drug disposition. Sugiyama and colleagues proposed the prediction of in vivo metabolic clearance in experimental animals and humans from in vitro biochemical parameters such as hepatic metabolism and plasma protein binding, based on anatomically and physiologically realistic pharmacokinetic models. However, there are few reports on interindividual variations as well as enzymatic kinetics (Vmax and Km values) in other drug-metabolizing enzymes, including cytosolic enzymes such as dihydropyrimidine dehydrogenase (DPD) and N-acetyltransferase (NAT). 5-Fluorouracil has been one of the most widely used anticancer drugs, and it is well documented that there is wide individual variation in both the tumor response and host toxicity associated with 5-fluorouracil. In addition, marked interindividual differences in the pharmacokinetic parameters of 5-fluorouracil have been reported. The primary metabolic pathway of this drug is the reduction to 5,6-dihydroflurouracil by DPD present in a liver cytosol fraction. After intravenous dosing to cancer patients, approximately 60—90% of the dose is excreted in urine within 24 h, primary as a-fluoro-b-alanine, indicating that 5-fluorouracil is mainly eliminated by metabolism. The major metabolic route of procainamide, a class I antiarrhythmic agent, is acetylation to N-acetylprocainamide, which is an active metabolite, and a wide variety in the amount of N-acetylprocainamide recovered after a dose of procainamide has been reported by different laboratories. Gibson et al. reported 7 to 34% N-acetylprocainamide recovery in 24 h in normal volunteers after a single oral dose of procainamide, and Karlsson et al. reported 6 to 53% recovery in 24 h in patients who were being given procainamide chronically. As mentioned above, there are large interindividual differences in the pharmacokinetics of 5-fluorouracil and procainamide, which are mainly eliminated by metabolism. Therefore, we investigated the enzymatic kinetics and interindividual variability of the metabolism of 5-fluorouracil and procainamide in human liver cytosol.