Abstract
Purpose. To identify the factors governing the dose-limiting toxicity in the gastrointestine (GI) and the antitumor activity after oral administration of capecitabine, a triple prodrug of 5-FU, in humans.
Method. The enzyme kinetic parameters for each of the four enzymes involved in the activation of capecitabine to 5-FU and its elimination were measured experimentally in vitro to construct a physiologically based pharmacokinetic model. Sensitivity analysis for each parameter was performed to identify the parameters affecting tissue 5-FU concentrations.
Results. The sensitivity analysis demonstrated that (i) the dihydropyrimidine dehydrogenase (DPD) activity in the liver largely determines the 5-FU AUC in the systemic circulation, (ii) the exposure of tumor tissue to 5-FU depends mainly on the activity of both thymidine phosphorylase (dThdPase) and DPD in the tumor tissues, as well as the blood flow rate in tumor tissues with saturation of DPD activity resulting in 5-FU accumulation, and (iii) the metabolic enzyme activity in the GI and the DPD activity in liver are the major determinants influencing exposure to 5-FU in the GI. The therapeutic index of capecitabine was found to be at least 17 times greater than that of other 5-FU-related anticancer agents, including doxifluridine, the prodrug of 5-FU, and 5-FU over their respective clinical dose ranges.
Conclusions. It was revealed that the most important factors that determine the selective production of 5-FU in tumor tissue after capecitabine administration are tumor-specific activation by dThdPase, the nonlinear elimination of 5-FU by DPD in tumor tissue, and the blood flow rate in tumors.
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REFERENCES
M. Miwa, M. Ura, M. Nishida, N. Sawada, T. Ishikawa, K. Mori, N. Shimma, I. Umeda, and H. Ishitsuka. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumors by enzymes concentrated in human liver and tumor tissue. Eur. J. Cancer 34:1274-1281 (1998).
R. B. Diaso and B. E. Harris. Clinical pharmacology of 5-fluorouracil. Pharmacokinetics 16:215-237 (1989).
S. P. Khor, H. Amyx, S. T. Davis, D. Nelson, D. P. Baccanari, and T. Spector. Dihydropyrimidine dehydrogenase inactivation and 5-fluorouracil pharmacokinetics: Allometric scaling of animal data, pharmacokinetics and toxicokinetics of 5-fluorouracil in humans. Cancer Chemother. Pharmacol. 39:233-238 (1997).
J. Schüler, J. Cassidy, E. Dumont, B. Roos, S. Durston, L. Banken, M. Utoh, K. Mori, E. Weidekamm, and B. Reigner. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother. Pharmacol. 45:291-297 (2000).
H. Onodera, I. Kuruma, H. Ishitsuka, and I. Horii. Pharmacokinetic study of capecitabine in monkeys and mice: Species differences in distribution of the enzyme responsible for its activation to 5-FU. Xenobiol. Metabol. Dispos 15:439-451 (2000).
T. Ishikawa, Y. Fukase, T. Yamamoto, F. Sekiguchi, and H. Ishitsuka. Antitumor activities of a novel fluoropyrimidine, N 4-pentyloxycarbonyl-5′-deoxy-5-fluorocytidine (capecitabine). Biol. Pharm. Bull. 21:713-717 (1998).
T. Ishikawa, M. Utoh, N. Sawada, M. Nishida, Y. Fukase, F. Sekiguchi, and H. Ishitsuka. Tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts. Biochem. Pharmacol. 55:1091-1097 (1998).
T. Ishikawa, F. Sekiguchi, Y. Fukase, N. Sawada, and H. Ishitsuka, Positive correlation between the efficacu of capecitabine and dosifluridine and the ratio of thymidine phsophorylase to dihydropymidine dehydorgenase activities in tumors in human cancer xenograft. Cancer Res. 58:685-690 (1998).
R. L. Dedrick. Animal scale up. J. Pharmacokinet. Biopharm. 1:435-461 (1973).
H. Boxenbaum. Interspecies variation in liver weight, hepatic blood flow, and antipyrine intrinsic clearance: extrapolation of data benzodiazepines and phenytoin. J. Biopharmacokinet. Biopharm. 8:165-176 (1980).
P. Vaupel, F. Kallinowski, and P. Okunieff. Blood flow, oxygen and nutrient supply, and metabolic microenviroment of human tumors: a review. Cancer Res. 49:6449-6465 (1989).
K. B. Bischoff, R. L. Dedrick, D. S. Zaharko, and J. A. Lonstreth. Methotrexate pharmacokientics. J. Pharm. Sci. 60:1128-1133 (1981).
K. K. Chan, J. L. Cohen, J. F. Gross, K. J. Himmelstein, J. R. Bateman, Y. Tsu-Lee, and A. Marlis. Prediction of adriamycine disposition in cancer patients using a physiologic, pharmacokinetic model. Cancer Treat. Rep. 62:1161-1171 (1978).
R. L. Dedrick, D. D. Forrester, J. N. Cannon, S. M. Dareer, and B. Mellett. Pharmacokinetics of 1-b-arabinofuranosyl cytosine (ARA-C) deamination in several species. Biochem. Pharmacol. 22:2405-2417 (1973).
K. S. Pang. A review of metabolite kinetics. J. Pharmacokinet. Biopharm. 13:633-662 (1985).
V. J. Stella and K. J. Himmelstein. Prodrug and site-specific drug delivery. J. Med. Chem. 23:1275-1282 (1980).
K. Shirai, I. Ohsawa, Y. Saito, and S. Yoshida. Effects of phospholipids on hydrolysis of trioleoylglycerol by human serum carboxylesterase. Biochim. Biophys. Acta 962:377-383 (1988)
J. H. Lin, Y. Sugiyama, S. Awazu, and M. Hanano. In vitro and in vivo evaluation of the tissue-to-blood partition coefficient for physiological pharmacokinetic models. J. Pharmacokinet. Biopharm. 10:637-647 (1982).
N. Benowitz, R. P. Forsyth, K. L. Melmon, and M. Rowland. Lidocaine disposition kinetics in monkey and man. I. Prediction by a perfusion model. Clin. Pharmacol. Ther. 16:87-98 (1974).
H. Zhu, R. J. Melder, L. T. Baxter, and R. K. Jain. Phsiologically based kinetic model of effect on cell biodistribution in mammals: implications for adoptive immunotherapy. Cancer Res. 56:3771-3781 (1996).
B. Davis and T. Morris. Physiological parameters in laboratory animals and humans. Pharm. Res. 10:1093-1095 (1993).
M. Chiba, M. Hensleigh, and J. H. Lin. Hepatic and intestinal metaboism of Indinavir, an HIV protease inhibitor, in rats and human microsomes, major role of CYP 3A. Biochem. Pharmacol. 53:1187-1195 (1997).
P. Klippert, P. Borm, and J. Noordhoek. Predition of intestinal first-pass effect of phenacetine in the rat from enzyme kinetic data—Correlation with in vivo data using mucosal blood flow. Biochem. Pharmacol. 31:2545-2548 (1982).
I. R. Judson, P. J. Beale, J. M. Trigo, W. Aherene, T. Cromptom, D. Jones, E. Bush, and B. Reigner. A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of 14C-labelled drug. Invest. New Drugs 17:49-56 (1999).
K. Mori, M. Hasegawa, M. Nishida, H. Toma, M. Fukuda, T. Kubota, N. Nasue, H. Yamana, H. K. Chung, T. Ikeda, K. Tkasaki, M. Oka, M. Kameyama, M. Toi, H. Fujii, M. Kitayamura, M. Murai, H. Sasaki, S. Ozono, H. Mukuuchi, Y. Shimada, Y. Onhishi, S. Aoyagi, K. Mizutani, M. Ogawa, A. Nakao, H. Kinoshita, T. Tono, H. Imanoto, Y. Nakashima, and T. Manabe. Espression levels of thymidine phosphorylase and dihydropyrimidine dehydrogenase in various human tumor tissues. Int. J. Oncol. 17:33-38 (2000).
A. S. E. Ojugo, P. M. J. McSheehy, M. Stubbs, G. Alder, C. L. Bashord, R. J. Maxwell, M. O. Leach, I. R. Judson, and J. R. Griffths. Influence of pH on the uptake of 5-fluorouracil into isolated tumor cell. Br. J. Cancer 77:873-879 (1998).
A. Hisaka and Y. Sugiyama. Analysis of nonlinear and nonsteady state hepatic ectraction with the dispersion model using the finite difference method. J. Phamacokinet. Biopharm. 26:495-519 (1998).
D. R. Budman, N. J. Meroopol, B. Reigner, P. J. Creaven, S. M. Lichtman, and E. Berghorn. Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine. J. Clin. Oncol. 16:1795-1802 (1998).
M. A. Villalona-Calero, G. R. Weiss, H. A. Burris, M. Kraynak, G. Rodrigues, R. L. Dregler, S. G. Eckhardt, B. Reigner, J. Moczygembra, H. U. Burger, T. Griffin, D. D. Von Hoff, and E. K. Rowinsky. Phase I and pharmacokinetic study of the oral fluoropyrimidine capecitabine in combination with paclitaxel in patients with advanced solid malignancies. J. Clin. Oncol. 17:1915-1925 (1999).
B. Reigner, J. Verweij, L. Dirix, J. Cassidy, C. Twelves, D. Allman, E. Weidekamm, B. Roos, L. Banken, M. Utoh, and B. Osterwalder. Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patients. Clin. Cancer Res. 4:941-948 (1998).
N. Sawada, T. Ishikawa, F. Sekiguchi, Y. Tanaka, and H. Ishitsuka. X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts. Clin. Cancer Res. 5:2948-2953 (1999).
M. Mackean, A. Planting, C. Twelves, J. Schellens, D. Allman, B. Osterwalder, B. Reigner, T. Griffin, S. Kaya, and J. Verweij. Phase I and pharmacologic study of intermittent twice-daily oral therapy with capoecitabine in patients with advanced and/or metastatic cancer. J. Clin. Oncol. 16:2977-2985
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Tsukamoto, Y., Kato, Y., Ura, M. et al. A Physiologically Based Pharmacokinetic Analysis of Capecitabine, a Triple Prodrug of 5-FU, in Humans: The Mechanism for Tumor-Selective Accumulation of 5-FU. Pharm Res 18, 1190–1202 (2001). https://doi.org/10.1023/A:1010939329562
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DOI: https://doi.org/10.1023/A:1010939329562