Ibrahim S S, Boudinot F D
Department of Pharmaceutics, College of Pharmacy, University of Georgia, Athens 30602.
J Pharm Pharmacol. 1989 Dec;41(12):829-34. doi: 10.1111/j.2042-7158.1989.tb06381.x.
The effects of dose on the pharmacokinetics of 2',3'-dideoxycytidine (DDC), a potent inhibitor of HIV replication, have been studied in rats. DDC was administered intravenously at doses of 10, 50, 100 and 200 mg kg-1. Plasma and urine drug concentrations were determined by HPLC. Non-compartmental pharmacokinetic parameters were calculated by area/moment analysis. DDC plasma concentrations declined rapidly with a terminal half-life of 0.98 +/- 0.18 h (mean +/- s.d.). No statistically significant differences were observed in pharmacokinetic parameters between the four doses. Total, renal and non-renal clearance values were independent of dose and averaged 1.67 +/- 0.24, 0.78 +/- 0.11, and 0.89 +/- 0.27 L h-1 kg-1, respectively. Approximately 50% of the dose was excreted unchanged in urine. Steady state volume of distribution was also independent of dose and averaged 1.2 +/- 0.21 L kg-1. Protein binding of DDC to rat serum proteins was independent of drug concentration with the fraction of drug bound averaging 0.45 +/- 0.12. Thus, the disposition pattern of DDC in the rat is independent of the administered dose even at high doses. Significant interspecies correlations were found for total, renal and non-renal clearance and steady state volume of distribution. Interspecies scaling resulted in superimposable plasma DDC concentration-time profiles from four laboratory animal species and man. Thus, plasma DDC concentrations in humans can be predicted from pharmacokinetic parameters obtained in laboratory animals.
已在大鼠中研究了剂量对2',3'-二脱氧胞苷（DDC，一种强效HIV复制抑制剂）药代动力学的影响。DDC以10、50、100和200 mg kg-1的剂量静脉给药。通过高效液相色谱法测定血浆和尿液中的药物浓度。通过面积/矩分析计算非房室药代动力学参数。DDC血浆浓度迅速下降，终末半衰期为0.98±0.18小时（平均值±标准差）。四个剂量之间的药代动力学参数未观察到统计学上的显著差异。总清除率、肾清除率和非肾清除率值与剂量无关，分别平均为1.67±0.24、0.78±0.11和0.89±0.27 L h-1 kg-1。约50%的剂量以原形从尿液中排泄。稳态分布容积也与剂量无关，平均为1.2±0.21 L kg-1。DDC与大鼠血清蛋白的蛋白结合与药物浓度无关，结合药物的分数平均为0.45±0.12。因此，即使在高剂量下，DDC在大鼠体内的处置模式也与给药剂量无关。在总清除率、肾清除率和非肾清除率以及稳态分布容积方面发现了显著的种间相关性。种间标度导致来自四种实验动物物种和人类的血浆DDC浓度-时间曲线重叠。因此，可以根据在实验动物中获得的药代动力学参数预测人类血浆中的DDC浓度。
