Hwang I Y, Elfarra A A
Department of Comperative Biosciences and Environmental Toxicology Center, University of Wisconsin, Madison.
J Pharmacol Exp Ther. 1991 Jul 1;258(1):171-7.
Recently, we have reported that S-(6-purinyl)-L-cysteine (PC) is a kidney-selective prodrug of 6-mercaptopurine. In the present study, the in vivo metabolism of PC and the biochemical basis of its renal selectivity were further investigated. In addition, several PC analogs were synthesized and evaluated as prodrugs of 6-mercaptopurine by determining the concentrations of 6-mercaptopurine and its metabolites, 6-methylmercaptopurine and 6-thiouric acid, in urine after rats were given the analogs. At 30 min after PC treatments, kidney metabolite concentrations were dependent on the PC dose at 40 to 130 mumol/kg and were not increased when a 400 mumol PC/kg dose was given. At the 400 mumol PC/kg dose, metabolite concentrations in the kidneys were higher at 30 min than at 1 or 3 hr, and were nearly 2.5- and 100-fold higher than those in liver and plasma, respectively. Rates of PC in vitro metabolism by liver and kidney cytosolic cysteine conjugate beta-lyases (beta-lyases) were similar, but metabolism by renal mitochondrial beta-lyase occurred at a 3-fold higher rate than the rate obtained with hepatic mitochondrial beta-lyase. When rats were given aminooxyacetic acid (500 mumol/kg) or probenecid (270 mumol/kg) before PC (130 mumol/kg), total kidney metabolite concentrations were reduced by 55 and 36%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
最近，我们报道了S-(6-嘌呤基)-L-半胱氨酸（PC）是6-巯基嘌呤的肾脏选择性前药。在本研究中，进一步研究了PC的体内代谢及其肾脏选择性的生化基础。此外，合成了几种PC类似物，并通过测定大鼠给予这些类似物后尿液中6-巯基嘌呤及其代谢物6-甲基巯基嘌呤和6-硫尿酸的浓度，将其作为6-巯基嘌呤的前药进行评估。PC处理后30分钟，肾脏代谢物浓度在40至130μmol/kg的PC剂量下依赖于PC剂量，给予400μmol PC/kg剂量时未增加。在400μmol PC/kg剂量下，肾脏中代谢物浓度在30分钟时高于1小时或3小时时，分别比肝脏和血浆中的浓度高近2.5倍和100倍。肝脏和肾脏胞质半胱氨酸共轭β-裂解酶（β-裂解酶）对PC的体外代谢速率相似，但肾脏线粒体β-裂解酶的代谢速率比肝脏线粒体β-裂解酶的代谢速率高3倍。当大鼠在给予PC（130μmol/kg）前给予氨氧基乙酸（500μmol/kg）或丙磺舒（270μmol/kg）时，肾脏总代谢物浓度分别降低了55%和36%。（摘要截短于250字）
