Fillastre J P, Godin M, Legallicier B, Chretien P, Bidault R, Gillotin C, Wooton R, Posner J, Peck R W
Department of Nephrology, University of Rouen, France.
J Antimicrob Chemother. 1996 May;37(5):965-74. doi: 10.1093/jac/37.5.965.
The pharmacokinetics of a single oral 200 mg dose of netivudine (1-(beta-D-arabinofuranosyl)-5-(1-propynyl)uracil), a nucleoside analogue under development for use in varicella zoster virus infections, were studied in 12 renal failure (RF) subjects (creatinine clearance 15 +/- 7 mL/min) and 12 age-matched healthy subjects with normal creatinine clearance. Blood and urine samples were collected up to nine days after drug administration. Concentrations of netivudine and of its main metabolite, the pyrimidine base 5-(1-propynyl)uracil (5 PU), were determined by a specific high performance liquid chromatography assay. The mean peak plasma concentrations of netivudine, Tmax, and volume of distribution were not significantly affected by RF. The elimination half-life of netivudine was approximately 15 h in subjects with normal renal function and 60 h in RF patients. Plasma and renal clearances of netivudine were significantly reduced in RF patients and AUC was three to four times higher in these patients. Cmax and AUC of 5 PU were higher in RF patients, and the half-life was also significantly longer. However, the half-life of this metabolite was much lower than that of the parent compound. Tmax and the lag time were similar in the two groups. There were highly significant correlations for netivudine and 5 PU between half-life and creatinine clearance and between renal clearance and creatinine clearance. These findings suggest that netivudine dosage may need to be reduced in patients with severe renal failure, and confirm that formation of the 5 PU is independent of the elimination of netivudine from plasma.
对12名肾衰竭（RF）患者（肌酐清除率为15±7 mL/分钟）和12名年龄匹配、肌酐清除率正常的健康受试者，研究了单次口服200 mg剂量奈替夫定（1-(β-D-阿拉伯呋喃糖基)-5-(1-丙炔基)尿嘧啶）的药代动力学。奈替夫定是一种正在研发用于治疗水痘带状疱疹病毒感染的核苷类似物。给药后九天内采集血液和尿液样本。通过特定的高效液相色谱分析法测定奈替夫定及其主要代谢产物嘧啶碱基5-(1-丙炔基)尿嘧啶（5 PU）的浓度。RF对奈替夫定的平均血浆峰浓度、达峰时间（Tmax）和分布容积没有显著影响。肾功能正常的受试者中奈替夫定的消除半衰期约为15小时，而RF患者中为60小时。RF患者中奈替夫定的血浆清除率和肾清除率显著降低，且这些患者的曲线下面积（AUC）高出三到四倍。RF患者中5 PU的峰浓度（Cmax）和AUC更高，其半衰期也显著更长。然而，该代谢产物的半衰期远低于母体化合物。两组的Tmax和滞后时间相似。奈替夫定和5 PU的半衰期与肌酐清除率之间以及肾清除率与肌酐清除率之间存在高度显著的相关性。这些发现表明，严重肾衰竭患者可能需要减少奈替夫定的剂量，并证实5 PU的形成与奈替夫定从血浆中的消除无关。
