新型抗癌药物β-L-二氧戊环胞苷在大鼠体内的临床前药代动力学

Preclinical pharmacokinetics of beta-L-dioxolane-cytidine, a novel anticancer agent, in rats.

作者信息

Moore L E, Boudinot F D, Chu C K

机构信息

Department of Pharmaecutics, College of Pharmacy, University of Georgia, Athens 30602-2353, USA.

出版信息

Cancer Chemother Pharmacol. 1997;39(6):532-6. doi: 10.1007/s002800050609.

DOI:10.1007/s002800050609

PMID:9118465

Abstract

PURPOSE

beta-L-Dioxolane-cytidine (OddC), a novel L-nucleoside analog with potent cytotoxicity in vitro, appears to be a promising candidate for anticancer therapy. In this study, a high performance liquid chromatography (HPLC) analytical method was developed and the preclinical pharmacokinetics of OddC were characterized in rats.

METHODS

Adult male Sprague Dawley rats were given 10, 25, or 50 mg/kg of OddC both intravenously and orally with a 6-day washout period between doses. Each rat received one dosage level of OddC and the route of administration was assessed by a randomized crossover design. Plasma and urine concentrations were determined by HPLC. Pharmacokinetic parameters were generated by area-moment analysis.

RESULTS

Following intravenous administration, the plasma concentrations of OddC declined rapidly in a biexponential manner with a terminal phase half-life of 1.65 +/- 1.12 h (mean +/- SD). Mean total, renal, and nonrenal clearances were 1.38 +/- 0.62, 0.30 +/- 0.14, and 1.08 +/- 0.59 1/h per kg. Approximately 22% of the administered dose was excreted unchanged in the urine. Thus, nonrenal clearance was the predominant route of elimination of OddC. The steady-state volume of distribution averaged 1.42 +/- 0.66 1/kg, indicating intracellular distribution of OddC. The nucleoside analog was slowly absorbed after oral administration and bioavailability varied greatly between individual rats, averaging 41 +/- 27% when calculated from urinary excretion data and 37 +/- 25% when calculated from plasma OddC concentration data.

CONCLUSION

The pharmacokinetics of OddC in rats were linear over the dose range studied.

摘要

目的

β-L-二氧戊环胞苷（OddC）是一种新型的L-核苷类似物，在体外具有强大的细胞毒性，似乎是抗癌治疗的一个有前景的候选药物。在本研究中，开发了一种高效液相色谱（HPLC）分析方法，并对OddC在大鼠中的临床前药代动力学进行了表征。

方法

成年雄性Sprague Dawley大鼠静脉内和口服给予10、25或50 mg/kg的OddC，剂量之间有6天的洗脱期。每只大鼠接受一个剂量水平的OddC，并通过随机交叉设计评估给药途径。通过HPLC测定血浆和尿液浓度。通过面积矩分析生成药代动力学参数。

结果

静脉给药后，OddC的血浆浓度以双指数方式迅速下降，终末相半衰期为1.65±1.12小时（平均值±标准差）。平均总清除率、肾清除率和非肾清除率分别为1.38±0.62、0.30±0.14和1.08±0.59 l/h per kg。约22%的给药剂量以原形从尿液中排出。因此，非肾清除是OddC消除的主要途径。平均稳态分布容积为1.42±0.66 l/kg，表明OddC在细胞内分布。口服给药后，该核苷类似物吸收缓慢，个体大鼠之间的生物利用度差异很大，根据尿排泄数据计算时平均为41±27%，根据血浆OddC浓度数据计算时平均为37±25%。