Interindividual variability in 5-Fluorouracil metabolism and procainamide N-acetylation in human liver cytosol.

We investigated the enzymatic kinetics and interindividual variability of the metabolism of 5-fluorouracil and procainamide by human liver cytosol and/or microsomes. The Km values for the 5-fluorouracil dihydropyrimidine dehydrogenase (DPD) and procainamide N-acetyltransferase activities in pooled liver cytosol, and procainamide hydrolysis in pooled liver microsomes were 3.9, 1670, and 969 microM, respectively, and the intrinsic clearance (Vmax/Km) values for these reactions were 128, 0.192, and 0.0059 microl/min/mg protein, respectively. The cytosolic activities of 5-fluorouracil metabolism and procainamide N-acetylation ranged from 145 to 790 (469+/-156, mean+/-S.D., n=22) and <1 to 152 (52+/-48, n=12) pmol/min/mg protein, respectively, and the DPD activity of 5-fluorouracil was neither gender-related nor age-dependent. Procainamide N-acetylation activities among 12 human cytosol samples were highly correlated with sulfamethazine N-acetylation activities, suggesting that procainamide N-acetylation is catalyzed by N-acetyltransferase-2. These results suggest that the N-acetylation reaction is more important than the hydrolysis in the metabolic pathway of procainamide, and that there are large interindividual differences in the enzyme activities towards the respective metabolic pathways of 5-fluorouracil and procainamide in human liver.

[1]  Y. Ohno,et al.  Interindividual variability in 2-hydroxylation, 3-sulfation, and 3-glucuronidation of ethynylestradiol in human liver. , 2004, Biological & pharmaceutical bulletin.

[2]  A. B. Kuilenburg,et al.  Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. , 2004 .

[3]  R Scott Obach,et al.  Drug metabolism and drug interactions: application and clinical value of in vitro models. , 2003, Current drug metabolism.

[4]  K. Omura.  Clinical implications of dihydropyrimidine dehydrogenase (DPD) activity in 5-FU-based chemotherapy: mutations in the DPD gene, and DPD inhibitory fluoropyrimidines , 2003, International Journal of Clinical Oncology.

[5]  H. Groen,et al.  Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene , 2002, British Journal of Cancer.

[6]  Y. Sugiyama,et al.  Prediction of in vivo drug-drug interactions based on mechanism-based inhibition from in vitro data: inhibition of 5-fluorouracil metabolism by (E)-5-(2-Bromovinyl)uracil. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[7]  D. Cross,et al.  A COMMENTARY ON THE USE OF HEPATOCYTES IN DRUG METABOLISM STUDIES DURING DRUG DISCOVERY AND DEVELOPMENT* , 2000, Drug metabolism reviews.

[8]  Y. Tanigawara,et al.  Genotyping of N‐acetylation polymorphism and correlation with procainamide metabolism , 1997, Clinical pharmacology and therapeutics.

[9]  T Iwatsubo,et al.  PREDICTION OF IN VIVO DRUG DISPOSITION FROM IN VITRO DATA BASED ON PHYSIOLOGICAL PHARMACOKINETICS , 1996, Biopharmaceutics & drug disposition.

[10]  F. Guengerich,et al.  Species- and gender-related differences in amine, alcohol and phenol sulphoconjugations. , 1995, Xenobiotica; the fate of foreign compounds in biological systems.

[11]  G. Milano,et al.  Dihydropyrimidine dehydrogenase (DPD) and clinical pharmacology of 5-fluorouracil (review). , 1994, Anticancer research.

[12]  H. Yamazaki,et al.  Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. , 1994, The Journal of pharmacology and experimental therapeutics.

[13]  T. Shimada,et al.  Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. , 1991, Chemical research in toxicology.

[14]  D. Grant,et al.  Monomorphic and polymorphic human arylamine N-acetyltransferases: a comparison of liver isozymes and expressed products of two cloned genes. , 1991, Molecular pharmacology.

[15]  A. Temellini,et al.  Interindividual variability in the glucuronidation and sulphation of ethinyloestradiol in human liver. , 1990, British journal of clinical pharmacology.

[16]  R. Diasio,et al.  Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. , 1987, Cancer research.

[17]  J. Bigger,et al.  Metabolism of procainamide in normal and cardiac subjects , 1976, Clinical pharmacology and therapeutics.

[18]  T. Gibson,et al.  Acetylation of procainamide in man and its relationship to isonicotinic acid hydrazide acetylation phenotype , 1975, Clinical pharmacology and therapeutics.

[19]  F. Sjöqvist,et al.  Acetylation of procaine amide in man studied with a new gas chromatographic method. , 1974, British journal of clinical pharmacology.

[20]  Oliver H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[21]  Y. Sugiyama,et al.  Quantitative prediction of in vivo drug clearance and drug interactions from in vitro data on metabolism, together with binding and transport. , 1998, Annual review of pharmacology and toxicology.

[22]  M Hosokawa,et al.  The mammalian carboxylesterases: from molecules to functions. , 1998, Annual review of pharmacology and toxicology.

[23]  T Nakagawa,et al.  A pharmacokinetic analysis program (multi) for microcomputer. , 1981, Journal of pharmacobio-dynamics.