Elfarra A A, Hwang I Y
Department of Comparative Biosciences, University of Wisconsin-Madison.
Drug Metab Dispos. 1993 Sep-Oct;21(5):841-5.
Previously, we have shown that 30 min after S-(6-purinyl)-L-cysteine (PC; 0.13 or 0.4 mmol/kg, ip) treatment of rats, kidney concentrations of 6-mercaptopurine (6-MP) and its further metabolites, 6-methylmercaptopurine and 6-thiouric acid, were nearly 2.4-fold higher than those in liver, and were nearly 90-fold higher than those in plasma. 6-MP was also detected in the urine of rats given the PC analogs, S-(6-purinyl)-N-acetyl-L-cysteine (NAPC), S-(6-purinyl)glutathione (PG), and S-(6-purinyl)-L-homocysteine (PHC). In this study, the kidney-selectivity of the PC analogs was investigated by determining the concentrations of 6-MP and its further metabolites in the kidney, liver, and plasma of rats given the analogs. After NAPC, PG, and PHC (0.8 mmol/kg, ip) treatments, kidney concentrations of total metabolites at 30 min were nearly 17.6-, 6.5-, and 2.9-fold higher than those in liver, respectively. Only trace amounts of metabolites were detected in plasma with any analog. After NAPC treatment (0.8 mmol/kg, ip) total metabolite concentrations in the kidney at 30 min were higher than those detected at 60 or 90 min. When the PC analogs were given at a lower dose (0.4 mmol/kg), only trace amounts of metabolites were detected in the kidney, and no metabolites were detected in liver or plasma. Rates of in vitro metabolism of PHC, PG, and NAPC to 6-MP by kidney homogenates were nearly 10.0, 6.7, and 0.3% of that measured with PC, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
此前，我们已表明，给大鼠腹腔注射S-(6-嘌呤基)-L-半胱氨酸（PC；0.13或0.4 mmol/kg）30分钟后，肾脏中6-巯基嘌呤（6-MP）及其进一步代谢产物6-甲基巯基嘌呤和6-硫尿酸的浓度比肝脏中的浓度高近2.4倍，比血浆中的浓度高近90倍。在给予PC类似物S-(6-嘌呤基)-N-乙酰-L-半胱氨酸（NAPC）、S-(6-嘌呤基)谷胱甘肽（PG）和S-(6-嘌呤基)-L-高半胱氨酸（PHC）的大鼠尿液中也检测到了6-MP。在本研究中，通过测定给予类似物的大鼠肾脏、肝脏和血浆中6-MP及其进一步代谢产物的浓度，研究了PC类似物的肾脏选择性。给予NAPC、PG和PHC（0.8 mmol/kg，腹腔注射）后，30分钟时肾脏中总代谢产物的浓度分别比肝脏中的浓度高近17.6倍、6.5倍和2.9倍。用任何一种类似物处理后，血浆中仅检测到微量代谢产物。给予NAPC（0.8 mmol/kg，腹腔注射）后，30分钟时肾脏中总代谢产物浓度高于60或90分钟时检测到的浓度。当以较低剂量（0.4 mmol/kg）给予PC类似物时，肾脏中仅检测到微量代谢产物，肝脏和血浆中未检测到代谢产物。肾脏匀浆将PHC、PG和NAPC体外代谢为6-MP的速率分别约为PC测定值的10.0%、6.7%和0.3%。（摘要截短于250字）
