Anderson B D, Morgan M E, Singhal D
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City 84112, USA.
Pharm Res. 1995 Aug;12(8):1126-33. doi: 10.1023/a:1016299507382.
6-Cl-2',3'-dideoxypurine (6-Cl-ddP), an adenosine deaminase (ADA) activated prodrug of ddI, may be an effective antiretroviral agent for the treatment of AIDS dementia due to its ability to deliver increased concentrations of ddI to brain tissue. To examine the feasibility of administering this drug orally, the oral and hepatic portal bioavailabilities of 6-Cl-ddP were determined. In addition, the oral and portal bioavailabilities of ddI after administration of the prodrug were compared to those from administration of ddI itself.
Pharmacokinetic and bioavailability studies were conducted in fully conscious, chronically catheterized rats in a randomized crossover design. Plasma ddI and 6-Cl-ddP concentration-time profiles were determined by HPLC.
6-Cl-ddP has poor apparent oral bioavailability (7% +/- 3%, n = 3) but high bioavailability after portal administration (97% +/- 11%), suggesting either poor absorption or extensive gut wall metabolism. The appearance of > 50% of the dose as ddI in the systemic circulation after an oral dose of 6-Cl-ddP rules out poor absorption of the prodrug, and confirms expectations of high ADA activity in the gastrointestinal tract. Gastric administration of 6-Cl-ddP resulted in a > 10-fold increase in the oral bioavailability of ddI, from 3-7% to > 50%, and a significant decrease in the variability in apparent bioavailability.
These data indicate that lipophilic adenosine deaminase activated prodrugs of dideoxypurine nucleosides may have limited utility for improving CNS delivery after oral administration but may be useful in enhancing the oral bioavailability of highly polar and therefore poorly absorbed dideoxynucleosides.
6-氯-2'，3'-双脱氧嘌呤（6-Cl-ddP）是双脱氧肌苷（ddI）的一种经腺苷脱氨酶（ADA）激活的前药，因其能够将更高浓度的ddI递送至脑组织，可能是一种治疗艾滋病痴呆的有效抗逆转录病毒药物。为了研究口服该药的可行性，测定了6-Cl-ddP的口服和肝门静脉生物利用度。此外，将前药给药后ddI的口服和门静脉生物利用度与ddI本身给药后的生物利用度进行了比较。
采用随机交叉设计，在完全清醒、长期插管的大鼠中进行药代动力学和生物利用度研究。通过高效液相色谱法测定血浆中ddI和6-Cl-ddP的浓度-时间曲线。
6-Cl-ddP的表观口服生物利用度较差（7%±3%，n = 3），但门静脉给药后生物利用度较高（97%±11%），这表明其吸收不佳或肠道壁代谢广泛。口服一剂6-Cl-ddP后，超过50%的剂量以ddI形式出现在体循环中，排除了前药吸收不佳的可能性，并证实了胃肠道中ADA活性较高的预期。胃内给予6-Cl-ddP使ddI的口服生物利用度提高了10倍以上，从3%-7%提高到>50%，且表观生物利用度的变异性显著降低。
这些数据表明，双脱氧嘌呤核苷的亲脂性腺苷脱氨酶激活前药在口服给药后改善中枢神经系统递送方面可能效用有限，但可能有助于提高高极性且因此吸收不佳的双脱氧核苷的口服生物利用度。
