Deguchi Y, Hayashi H, Fujii S, Naito T, Yokoyama Y, Yamada S, Kimura R
Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
J Drug Target. 2000;8(6):371-81. doi: 10.3109/10611860008997913.
1,3-Diacetyl-2-ketoprofen glyceride (DAKG), a prodrug of ketoprofen, was synthesized as a model compound in our attempt to develop a central nervous system (CNS) drug delivery system to treat Alzheimer's disease. The primary purpose of the present study is to test whether DAKG improves the delivery of ketoprofen to the brain and to quantitatively evaluate several factors that influence the brain distribution of this prodrug. ddY mice were injected with either ketoprofen or DAKG at a dose of 40 micromol/kg and then the plasma and brain pharmacokinetics of these agents were assessed. The brain uptake clearance of ketoprofen and DAKG across the BBB was measured by in situ mouse brain perfusion. In addition, the efflux permeability of ketoprofen through the BBB was evaluated using the in vivo mouse brain microdialysis technique. The in vivo metabolism of DAKG in the brain was assessed by a short infusion into the internal carotid artery coupled with the brain metabolism index (BMI) method. Administration of DAKG produced an approximately 3-fold increase in the area under the brain concentration - time curve of ketoprofen, compared with administration of ketoprofen itself. The brain uptake clearance (CL(in) ) of ketoprofen across the BBB was 0.0308 +/- 0.0046 mL/min/g whereas the CL(in) of DAKG was 1.60 +/- 0.16 mL/min/g, suggesting a marked increase in BBB permeability following lipidization of ketoprofen. The BMI method confirmed that DAKG is taken up by the brain to rapidly release ketoprofen in a dose-dependent manner. The in vitro metabolism studies revealed that isolated bovine brain capillaries as well as whole brain homogenate have the hydrolysis activity to DAKG. In addition, the brain concentration of ketoprofen after DAKG administration was maintained for a significant period following co-administration of probenecid. These results suggest that DAKG improves the delivery of ketoprofen to the brain, and this improved delivery is due to avid uptake of DAKG across the BBB followed by rapid hydrolysis to ketoprofen within the brain. The ketoprofen produced in the brain was probably cleared by the active efflux system operating in the BBB. Significant inhibition of this efflux system by co-administration of probenecid could result in a sustained concentration of ketoprofen in the brain following DAKG administration.
1,3 - 二乙酰 - 2 - 酮洛芬甘油酯（DAKG）是酮洛芬的前体药物，作为一种模型化合物被合成出来，旨在开发一种用于治疗阿尔茨海默病的中枢神经系统（CNS）给药系统。本研究的主要目的是测试DAKG是否能改善酮洛芬向脑内的递送，并定量评估影响该前体药物脑内分布的几个因素。给ddY小鼠以40微摩尔/千克的剂量注射酮洛芬或DAKG，然后评估这些药物的血浆和脑药代动力学。通过原位小鼠脑灌注测量酮洛芬和DAKG穿过血脑屏障（BBB）的脑摄取清除率。此外，使用体内小鼠脑微透析技术评估酮洛芬通过BBB的外排通透性。通过向颈内动脉短时间输注并结合脑代谢指数（BMI）方法评估DAKG在脑内的体内代谢。与单独给予酮洛芬相比，给予DAKG使酮洛芬的脑浓度 - 时间曲线下面积增加了约3倍。酮洛芬穿过BBB的脑摄取清除率（CL(in)）为0.0308±0.0046毫升/分钟/克，而DAKG的CL(in)为1.60±0.16毫升/分钟/克，这表明酮洛芬脂化后BBB通透性显著增加。BMI方法证实DAKG被脑摄取并以剂量依赖方式快速释放酮洛芬。体外代谢研究表明，分离的牛脑微血管以及全脑匀浆对DAKG具有水解活性。此外，在给予丙磺舒后，给予DAKG后酮洛芬的脑浓度在相当长的一段时间内得以维持。这些结果表明，DAKG改善了酮洛芬向脑内的递送，这种改善的递送是由于DAKG通过BBB的大量摄取，随后在脑内快速水解为酮洛芬。脑内产生的酮洛芬可能通过BBB中运行的主动外排系统清除。丙磺舒联合给药对该外排系统的显著抑制可能导致给予DAKG后酮洛芬在脑内的浓度持续存在。
