Yang Jerry Z, Chen Weiqing, Borchardt Ronald T
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047, USA.
J Pharmacol Exp Ther. 2002 Nov;303(2):840-8. doi: 10.1124/jpet.102.037135.
In vitro stability and in vivo pharmacokinetic studies of a model opioid peptide, H-Tyr-D-Ala-Gly-Phe-D-Leu-OH (DADLE), and its cyclic prodrugs (acyloxyalkoxy-based cyclic prodrug of DADLE, coumarinic acid-based cyclic prodrug of DADLE, and oxymethyl-modified coumarinic acid-based cyclic prodrug of DADLE) were conducted. The enzymatic stability of DADLE and its prodrugs in various biological media was determined at 37 degrees C in the presence and absence of paraoxon, a known esterase inhibitor. The prodrugs exhibited metabolic stability to exo- and endopeptidases, and esterase-catalyzed bioconversion of the prodrugs to DADLE was observed. For pharmacokinetic studies in rats, various biological samples (blood, bile, urine, and brain) were collected after i.v. administration of DADLE and its prodrugs. The samples were analyzed by high-performance liquid chromatography with tandem mass spectrometric detection, and the conversion from the prodrugs to intermediates to DADLE was monitored. The prodrugs exhibited similar pharmacokinetic properties and showed improved stability compared with DADLE in rat blood. This increased stability led to higher plasma concentrations of DADLE after i.v. administration of the prodrugs compared with i.v. administration of DADLE alone. In terms of elimination pathways, metabolism by endopeptidases was the major route for DADLE elimination, whereas rapid biliary excretion was the major route of elimination for the prodrugs. The rapid elimination of the prodrugs by the liver and the formation of stable intermediates after esterase hydrolysis limited the bioconversion efficiencies of the prodrugs to DADLE after i.v. administration. The substrate activity of the prodrugs for efflux transporters (e.g., P-glycoprotein) in the blood-brain barrier significantly restricted their access to the brain.
对一种模型阿片肽H-Tyr-D-Ala-Gly-Phe-D-Leu-OH（DADLE）及其环型前药（基于酰氧基烷氧基的DADLE环型前药、基于香豆酸的DADLE环型前药以及基于氧甲基修饰香豆酸的DADLE环型前药）进行了体外稳定性和体内药代动力学研究。在37℃下，于存在和不存在对氧磷（一种已知的酯酶抑制剂）的情况下，测定了DADLE及其前药在各种生物介质中的酶稳定性。这些前药对外肽酶和内肽酶表现出代谢稳定性，并且观察到酯酶催化前药生物转化为DADLE。在大鼠体内进行药代动力学研究时，静脉注射DADLE及其前药后收集了各种生物样品（血液、胆汁、尿液和脑）。通过高效液相色谱-串联质谱检测对样品进行分析，并监测从前药到中间体再到DADLE的转化。与DADLE相比，这些前药在大鼠血液中表现出相似的药代动力学特性且稳定性有所提高。这种增加的稳定性导致静脉注射前药后DADLE的血浆浓度高于单独静脉注射DADLE时的浓度。在消除途径方面，内肽酶代谢是DADLE消除的主要途径，而快速胆汁排泄是前药消除的主要途径。肝脏对前药的快速消除以及酯酶水解后形成稳定的中间体限制了静脉注射后前药向DADLE的生物转化效率。前药作为血脑屏障中流出转运体（例如P-糖蛋白）的底物的活性显著限制了它们进入脑内。
