Fractionated administration of high-dose cyclophosphamide: influence on dose-dependent changes in pharmacokinetics and metabolism

被引:36
作者
Busse, D
Busch, FW
Schweizer, E
Bohnenstengel, F
Eichelbaum, M
Fischer, P
Schumacher, K
Aulitzky, WE
Kroemer, HK
机构
[1] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany
[2] Robert Bosch Krankenhaus, Zentrum Innere Med, Abt Hamatol & Onkol, D-70376 Stuttgart, Germany
[3] Univ Stuttgart, Inst Organ Chem & Isotopenforsch, D-70569 Stuttgart, Germany
关键词
cyclophosphamide; high dose; pharmacokinetics; application schedule;
D O I
10.1007/s002800050893
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: The alkylating agent cyclophosphamide (CP) is a prodrug that is metabolized to both cytotoxic and inactive compounds. We have previously shown that following dose escalation from conventional-dose (CD) to high-dose (HD) levels; the fraction of the dose cleared by bioactivation is significantly decreased (66% versus 48.5%) in favor of inactivating elimination pathways when the HD is given as a single I-h infusion. Based on the concept of bioactivating enzyme saturation with increasing doses, we investigated the influence of fractionated application of HD-CP on dose-dependent changes in metabolism. Parients and methods: Plasma concentrations of CP (measured by high-performance liquid chromatography, HPLC) and urinary concentrations of CP and its major metabolites (quantified by [P-31]-nuclear magnetic resonance spectroscopy; [P-31]-NMR spectroscopy), were determined in four patients with high-risk primary breast cancer who received adjuvant chemotherapy including both CD-CP (500 mg/m(2) infused over 1 h) and split HD-CP (50 mg/kg infused over 1 h on each of 2 consecutive days (d): d(1) and d(2). Results: (Data are given as mean values for CD and d(1)/d(2) of HD, respectively). Systemic clearance (CL) of CP was similar during CD and d(1) of HD, but significantly increased on d(2) of HD (CL: 83 and 78/115 ml/min; P ( 0.01 for dl versus d2) The latter was translated into an increase in formation CL of both active (+16.3 ml/min) and inactive metabolites (+ 17.6 ml/min) and reflects autoinduction of metabolism. As compared with CD-CP, no statistically significant de crease was observed in the relative contribution of bio activation CL to overall CL during both days of HD (63% versus 57%/53%). Recovery of intact CP in 24-h urine corresponded to 24%, 29%, 32% of the dose (P < 0.05 for d(1) versus d(2) of HD). Conclusions: Following dose escalation of CP, dividing the high dose over 2 days instead of one single infusion may favorably impact the metabolism of CP in terms of bioactivation. In addition, on day 2 of a split regimen, renal elimination of CP is decreased, which implies that more drug is available for metabolism.
引用
收藏
页码:263 / 268
页数:6
相关论文
共 32 条
[1]   A PHASE-II STUDY OF HIGH-DOSE CYCLOPHOSPHAMIDE, THIOTEPA, AND CARBOPLATIN WITH AUTOLOGOUS MARROW SUPPORT IN WOMEN WITH MEASURABLE ADVANCED BREAST-CANCER RESPONDING TO STANDARD-DOSE THERAPY [J].
ANTMAN, K ;
AYASH, L ;
ELIAS, A ;
WHEELER, C ;
HUNT, M ;
EDER, JP ;
TEICHER, BA ;
CRITCHLOW, J ;
BIBBO, J ;
SCHNIPPER, LE ;
FREI, E .
JOURNAL OF CLINICAL ONCOLOGY, 1992, 10 (01) :102-110
[2]   CYCLOPHOSPHAMIDE PHARMACOKINETICS - CORRELATION WITH CARDIAC TOXICITY AND TUMOR RESPONSE [J].
AYASH, LJ ;
WRIGHT, JE ;
TRETYAKOV, O ;
GONIN, R ;
ELIAS, A ;
WHEELER, C ;
EDER, JP ;
ROSOWSKY, A ;
ANTMAN, K ;
FREI, E .
JOURNAL OF CLINICAL ONCOLOGY, 1992, 10 (06) :995-1000
[3]  
BAGLEY CM, 1973, CANCER RES, V33, P226
[4]   RETRACTED: HIGH-DOSE CHEMOTHERAPY WITH HEMATOPOIETIC RESCUE AS PRIMARY-TREATMENT FOR METASTATIC BREAST-CANCER - A RANDOMIZED TRIAL (Retracted article. See vol. 19, pg. 2973, 2001) [J].
BEZWODA, WR ;
SEYMOUR, L ;
DANSEY, RD .
JOURNAL OF CLINICAL ONCOLOGY, 1995, 13 (10) :2483-2489
[5]  
Bitran JD, 1996, BONE MARROW TRANSPL, V17, P157
[6]  
BODDY AV, 1995, CANCER CHEMOTH PHARM, V36, P53
[7]   Characterization of the cytochrome P450 involved in side-chain oxidation of cylophosphamide in humans [J].
Bohnenstengel, F ;
Hofmann, U ;
Eichelbaum, M ;
Kroemer, HK .
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1996, 51 (3-4) :297-301
[8]  
Bohnenstengel F., 1996, Naunyn-Schmiedeberg's Archives of Pharmacology, V353, pR158
[9]  
BOHNENSTENGEL F, 1997, N-S ARCH PHARMACOL, V355, pR123
[10]   Dose escalation of cyclophosphamide in patients with breast cancer: Consequences for pharmacokinetics and metabolism [J].
Busse, D ;
Busch, FW ;
Bohnenstengel, F ;
Eichelbaum, M ;
Fischer, P ;
Opalinska, J ;
Schumacher, K ;
Schweizer, E ;
Kroemer, HK .
JOURNAL OF CLINICAL ONCOLOGY, 1997, 15 (05) :1885-1896