Parang K, Wiebe L I, Knaus E E
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
J Pharm Pharmacol. 1998 Sep;50(9):989-96. doi: 10.1111/j.2042-7158.1998.tb06913.x.
The in-vivo biodistribution and pharmacokinetics in mice of 3'-azido-2',3'-dideoxythymidine (1, AZT), 2-bromomyristic acid (2) and their common prodrug, (+/-)-3'-azido-2',3'-dideoxy-5'-O-(2-bromomyristoyl)thymidine (3) are reported. The objectives of the work were to enhance the anti-human immunodeficiency virus and anti-fungal effects of 1 and 2 by improving their delivery to the brain and liver. The pharmacokinetics of AZT (beta t1/2 (elimination, or beta-phase, half-life) = 112.5 min; AUC (area under the plot of concentration against time) = 29.1 +/- 2.9 micromol g(-1) min; CL (blood clearance) = 10.5 +/- 1.1 mL min(-1) kg(-1)) and its ester prodrug (3, beta t1/2 = 428.5 min; AUC = 17.3 +/- 4.7 micromol g(-1) min; CL = 17.6 +/- 4.8 mL min(-1) kg(-1) were compared after intravenous injection of equimolar doses (0.3 mmol kg(-1)) via the tail vein of Balb/c mice (25-30 g). The prodrug was rapidly converted to AZT in-vivo, but plasma levels of AZT (peak concentration 0.17 micromol g(-1)) and AUC (12.3 micromol min g(-1)) were lower than observed after AZT administration (peak concentration 0.36 micromol g(-1); AUC 29.1 micromol min g(-1). The prodrug also accumulated rapidly in the liver immediately after injection, resulting in higher concentrations of AZT than observed after administration of AZT itself (respective peak concentrations 1.11 and 0.81 micromol g(-1); respective AUCs 42.5 and 12.7 micromol min g(-1)). Compared with doses of AZT itself, 3 also led to significantly higher brain concentration of AZT (25.7 compared with 9.8 nmol g(-1)) and AUCs (2.8 compared with 1.4 micromol min g(-1)). At the doses used in this study the antifungal agent 2-bromomyristic acid was measurable in plasma and brain within only 2 min of injection. Hepatic concentrations of 2-bromomyristic acid were higher for at least 2 h after dosing with 3 than after dosing with the acid itself. In summary, comparative biodistribution studies of AZT and its prodrug showed that the prodrug led to higher concentrations of AZT in the brain and liver. Although the prodrug did not result in measurably different concentrations of 2-bromomyristic acid in the blood and brain, it did lead to levels in the liver which were higher than those achieved by dosing with the acid itself.
报道了3'-叠氮基-2',3'-双脱氧胸苷（1，齐多夫定）、2-溴肉豆蔻酸（2）及其共同前药（±）-3'-叠氮基-2',3'-双脱氧-5'-O-（2-溴肉豆蔻酰基）胸苷（3）在小鼠体内的生物分布和药代动力学。该研究的目的是通过改善1和2向脑和肝的递送，增强它们的抗人类免疫缺陷病毒和抗真菌作用。经尾静脉向体重25 - 30 g的Balb/c小鼠静脉注射等摩尔剂量（0.3 mmol kg⁻¹）后，比较了齐多夫定（βt1/2（消除或β相半衰期）= 112.5分钟；AUC（浓度-时间曲线下面积）= 29.1 ± 2.9 μmol g⁻¹ min；CL（血液清除率）= 10.5 ± 1.1 mL min⁻¹ kg⁻¹）及其酯前药（3，βt1/2 = 428.5分钟；AUC = 17.3 ± 4.7 μmol g⁻¹ min；CL = 17.6 ± 4.8 mL min⁻¹ kg⁻¹）的药代动力学。前药在体内迅速转化为齐多夫定，但齐多夫定的血浆水平（峰值浓度0.17 μmol g⁻¹）和AUC（12.3 μmol min g⁻¹）低于给予齐多夫定后观察到的水平（峰值浓度0.36 μmol g⁻¹；AUC 29.1 μmol min g⁻¹）。注射后，前药也迅速在肝脏中蓄积，导致齐多夫定的浓度高于给予齐多夫定本身后观察到的浓度（各自的峰值浓度分别为1.11和0.81 μmol g⁻¹；各自的AUC分别为42.5和12.7 μmol min g⁻¹）。与给予齐多夫定本身的剂量相比，3也导致脑内齐多夫定的浓度显著更高（分别为25.7和9.8 nmol g⁻¹）以及AUC更高（分别为2.8和1.4 μmol min g⁻¹）。在本研究使用的剂量下，抗真菌剂2-溴肉豆蔻酸在注射后仅2分钟内即可在血浆和脑中检测到。给予3后，肝脏中2-溴肉豆蔻酸的浓度在给药后至少2小时内高于给予该酸本身后。总之，齐多夫定及其前药的比较生物分布研究表明，前药可使脑和肝脏中齐多夫定的浓度更高。尽管前药在血液和脑中未导致2-溴肉豆蔻酸的浓度有明显差异，但它确实使肝脏中的水平高于给予该酸本身所达到的水平。
