Lupia R H, Ferencz N, Lertora J J, Aggarwal S K, George W J, Agrawal K C
Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112.
Antimicrob Agents Chemother. 1993 Apr;37(4):818-24. doi: 10.1128/AAC.37.4.818.
The pharmacokinetics of two prodrugs of zidovudine (AZT), 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester and isoleucinyl ester (DPAZT and IAZT, respectively), were investigated in a rabbit model to determine their potential utility as drugs against human immunodeficiency virus. Drugs were administered by intravenous infusion over 5 min at doses equal to 10 mg of AZT per kg of body weight. The levels of the prodrugs and of released AZT in plasma, cerebrospinal fluid (CSF), and brain were determined by high-performance liquid chromatography analysis. DPAZT disappeared rapidly from plasma, whereas IAZT maintained a sustained level in plasma for up to 4 h. The levels in plasma of AZT released from DPAZT were consistently lower than the levels of AZT released from IAZT or AZT itself. At 75 min after infusion of AZT, DPAZT, and IAZT, the CSF plasma AZT ratios were 0.23, 0.30, and 0.25, while the brain/CSF AZT ratios were 0.32, 0.63, and 0.64, respectively. These results indicate that the administration of each of the prodrugs produced a higher concentration of AZT in the brain than did the direct administration of AZT. Both prodrugs therefore may be superior to AZT itself with respect to achieving anti-human immunodeficiency virus concentrations within the central nervous system.
研究了齐多夫定（AZT）的两种前药1,4 - 二氢 - 1 - 甲基 - 3 - [(吡啶甲酰基)氧基]酯和异亮氨酰酯（分别为DPAZT和IAZT）在兔模型中的药代动力学，以确定它们作为抗人类免疫缺陷病毒药物的潜在效用。药物通过静脉输注在5分钟内给药，剂量相当于每千克体重10毫克AZT。通过高效液相色谱分析测定血浆、脑脊液（CSF）和脑中前药及释放的AZT的水平。DPAZT从血浆中迅速消失，而IAZT在血浆中维持长达4小时的持续水平。从DPAZT释放的AZT的血浆水平始终低于从IAZT或AZT本身释放的AZT的水平。在输注AZT、DPAZT和IAZT后75分钟，CSF/血浆AZT比值分别为0.23、0.30和0.25，而脑/CSF AZT比值分别为0.32、0.63和0.64。这些结果表明，与直接给予AZT相比，给予每种前药在脑中产生的AZT浓度更高。因此，就实现中枢神经系统内的抗人类免疫缺陷病毒浓度而言，两种前药可能都优于AZT本身。
