This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ikeda, K. Articles by Kawaguchi, Y. Search for Related Content PubMed PubMed Citation Articles by Ikeda, K. Articles by Kawaguchi, Y.

Bioactivation of Tegafur to 5-Fluorouracil Is Catalyzed by Cytochrome P-450 2A6 in Human Liver Microsomes in Vitro¹

Pharmacokinetics Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., Tokushima 771-0194, Japan [K. I., K. Y., E. M., S. N., Y. K.]; Toxicological Laboratory, SRI International, CA 94025-3493 [C. A. T.]; and Laboratory of Biochemical Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan [K. K., K. C.]

ABSTRACT

Tegafur is a prodrug of 5-fluorouracil (5-FU) consisting of a new class of oral chemotherapeutic agents, tegafur/uracil and S-1, which are classified as dihydropyrimidine dehydrogenase inhibitory fluoropyrimidines. It is bioactivated to 5-FU via 5'-hydroxylation mediated by cytochrome P-450 (CYP). However, which isoform(s) of CYP is responsible for the bioactivation process of tegafur remains unclear. The purpose of the present study was to identify the human CYP isoform(s) involved in the metabolic activation of tegafur using human liver microsomes and cDNA-expressed human CYPs.

The formation of 5-FU from tegafur in human liver microsomes showed biphase kinetics with K_m and V_max values for the high-affinity component of 0.43 ± 0.05 mM and 4.02 ± 1.70 nmol/mg/min (mean ± SD, n = 4), respectively. In the correlation study using a panel of 10 human liver microsomes, the formation of 5-FU from tegafur showed a significant correlation (r = 0.98; P < 0.001) with coumarin 7-hydroxylation, a marker activity of CYP2A6. In addition, a specific substrate of CYP2A6 and anti-CYP2A6 antibody inhibited the formation of 5-FU by 90% in human liver microsomes. Moreover, cDNA-expressed CYP2A6 showed the highest activity for the formation of 5-FU among 10 cDNA-expressed CYPs, with a K_m value similar to that found for the high-affinity component in human liver microsomes.

These findings clearly suggest that CYP2A6 is a principal enzyme responsible for the bioactivation process of tegafur in human liver microsomes. However, to what extent the bioactivation of tegafur by CYP2A6 accounts for the formation of 5-FU in vivo remains unclear, because the formation of 5-FU from tegafur is also catalyzed by the soluble fraction of a 100,000 x g supernatant and also derived from spontaneous degradation of tegafur.

This article has been cited by other articles:

				K. Fujita, H. Nakayama, W. Ichikawa, W. Yamamoto, H. Endo, F. Nagashima, R. Tanaka, T. Miya, Y. Sunakawa, K. Yamashita, et al. Pharmacokinetics of 5-Fluorouracil in Elderly Japanese Patients with Cancer Treated with S-1 (a Combination of Tegafur and Dihydropyrimidine Dehydrogenase Inhibitor 5-Chloro-2,4-dihydroxypyridine) Drug Metab. Dispos., July 1, 2009; 37(7): 1375 - 1377. [Abstract] [Full Text] [PDF]

				K. Fujita, W. Ichikawa, W. Yamamoto, H. Endo, F. Nagashima, R. Tanaka, T. Miya, K. Araki, K. Kodama, Y. Sunakawa, et al. Fixed dosing and pharmacokinetics of S-1 in Japanese cancer patients with large body surface areas Ann. Onc., May 1, 2009; 20(5): 946 - 949. [Abstract] [Full Text] [PDF]

				T. Shirasaka Development History and Concept of an Oral Anticancer Agent S-1 (TS-1(R)): Its Clinical Usefulness and Future Vistas Jpn. J. Clin. Oncol., January 1, 2009; 39(1): 2 - 15. [Abstract] [Full Text] [PDF]

				J. L. Yen-Revollo, R. M. Goldberg, and H. L. McLeod Can Inhibiting Dihydropyrimidine Dehydrogenase Limit Hand-Foot Syndrome Caused by Fluoropyrimidines? Clin. Cancer Res., January 1, 2008; 14(1): 8 - 13. [Abstract] [Full Text] [PDF]

				K. Yokoo, A. Hamada, H. Watanabe, T. Matsuzaki, T. Imai, H. Fujimoto, K. Masa, T. Imai, and H. Saito Involvement of Up-Regulation of Hepatic Breast Cancer Resistance Protein in Decreased Plasma Concentration of 7-Ethyl-10-hydroxycamptothecin (SN-38) by Coadministration of S-1 in Rats Drug Metab. Dispos., September 1, 2007; 35(9): 1511 - 1517. [Abstract] [Full Text] [PDF]

				J. A. Ajani, J. Faust, K. Ikeda, J. C. Yao, H. Anbe, K. L. Carr, M. Houghton, and P. Urrea Phase I Pharmacokinetic Study of S-1 Plus Cisplatin in Patients With Advanced Gastric Carcinoma J. Clin. Oncol., October 1, 2005; 23(28): 6957 - 6965. [Abstract] [Full Text] [PDF]

				M. Rooseboom, J. N. M. Commandeur, and N. P. E. Vermeulen Enzyme-Catalyzed Activation of Anticancer Prodrugs Pharmacol. Rev., March 1, 2004; 56(1): 53 - 102. [Abstract] [Full Text] [PDF]