Kidney-selective prodrugs of 6-mercaptopurine: biochemical basis of the kidney selectivity of S-(6-purinyl)-L-cysteine and metabolism of new analogs in rats.
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)
Hwang
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Department of Comperative Biosciences and Environmental Toxicology Center, University of Wisconsin, Madison.
Elfarra
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D000625:Aminooxyacetic Acid / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D007668:Kidney / Q000378:metabolism*; D008297:Male; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D011339:Probenecid / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D011355:Prodrugs; C061748:S-(6-purinyl)cysteine; D000625:Aminooxyacetic Acid; D015122:Mercaptopurine; D011339:Probenecid