Targeting of 6-mercaptopurine to the kidneys. Metabolism and kidney-selectivity of S-(6-purinyl)-L-cysteine analogs in rats.
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)
Elfarra
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Department of Comparative Biosciences, University of Wisconsin-Madison.
Hwang
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IY
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001711:Biotransformation; D006710:Homocysteine / Q000031:analogs & derivatives / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008190:Lyases / Q000378:metabolism; D008297:Male; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D009928:Organ Specificity; D011355:Prodrugs / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014527:Uric Acid / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism
D011355:Prodrugs; D006710:Homocysteine; C061748:S-(6-purinyl)cysteine; C084451:S-(6-purinyl)-N-acetylcysteine; C084452:S-(6-purinyl)homocysteine; D014527:Uric Acid; C014632:2-keto-4-methylthiobutyric acid; C010240:6-methylthiopurine; C010352:6-thiouric acid; D008715:Methionine; D015122:Mercaptopurine; D008190:Lyases; D000111:Acetylcysteine