A physiologically based pharmacokinetic analysis of capecitabine, a triple prodrug of 5-FU, in humans: The mechanism for tumor-selective accumulation of 5-FU

被引:65
作者
Tsukamoto, Y
Kato, Y
Ura, M
Horii, I
Ishitsuka, H
Kusuhara, H
Sugiyama, Y [1 ]
机构
[1] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan
[2] Nippon Roche Res Ctr, Dept Preclin Sci, Kamakura, Kanagawa 2478530, Japan
[3] Nippon Roche Res Ctr, Dept Oncol, Kamakura, Kanagawa 2478530, Japan
关键词
physiologically based pharmacokinetic model; capecitabine; 5-FU; tumor selective accumulation; blood flow rate;
D O I
10.1023/A:1010939329562
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Purpose. To identify the factors governing the dose-limiting toxicity in the gastrointestine (Gl) 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 Ever lar.-cly 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.
引用
收藏
页码:1190 / 1202
页数:13
相关论文
共 32 条
[1]  
BENOWITZ N, 1974, CLIN PHARMACOL THER, V16, P87
[2]   METHOTREXATE PHARMACOKINETICS [J].
BISCHOFF, KB ;
DEDRICK, RL ;
ZAHARKO, DS ;
LONGSTRETH, JA .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1971, 60 (08) :1128-+
[3]   INTERSPECIES VARIATION IN LIVER WEIGHT, HEPATIC BLOOD-FLOW, AND ANTIPYRINE INTRINSIC CLEARANCE - EXTRAPOLATION OF DATA TO BENZODIAZEPINES AND PHENYTOIN [J].
BOXENBAUM, H .
JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS, 1980, 8 (02) :165-176
[4]   Preliminary studies of a novel oral fluoropyrimidine carbamate: Capecitabine [J].
Budman, DR ;
Meropol, NJ ;
Reigner, B ;
Creaven, PJ ;
Lichtman, SM ;
Berghorn, E ;
Behr, J ;
Gordon, RJ ;
Osterwalder, B ;
Griffin, T .
JOURNAL OF CLINICAL ONCOLOGY, 1998, 16 (05) :1795-1802
[5]  
CHAN KK, 1978, CANCER TREAT REP, V62, P1161
[6]   Hepatic and intestinal metabolism of indinavir, an HIV protease inhibitor, in rat and human microsomes - Major role of CYP3A [J].
Chiba, M ;
Hensleigh, M ;
Lin, JH .
BIOCHEMICAL PHARMACOLOGY, 1997, 53 (08) :1187-1195
[7]   PHYSIOLOGICAL-PARAMETERS IN LABORATORY-ANIMALS AND HUMANS [J].
DAVIES, B ;
MORRIS, T .
PHARMACEUTICAL RESEARCH, 1993, 10 (07) :1093-1095
[8]   ANIMAL SCALE-UP [J].
DEDRICK, RL .
JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS, 1973, 1 (05) :435-460
[9]   PHARMACOKINETICS OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE (ARA-C) DEAMINATION IN SEVERAL SPECIES [J].
DEDRICK, RL ;
FORRESTER, DD ;
CANNON, JN ;
DAREER, SME ;
MELLETT, LB .
BIOCHEMICAL PHARMACOLOGY, 1973, 22 (19) :2405-2417
[10]   CLINICAL-PHARMACOLOGY OF 5-FLUOROURACIL [J].
DIASIO, RB ;
HARRIS, BE .
CLINICAL PHARMACOKINETICS, 1989, 16 (04) :215-237