Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 102, Issue 3, Pages 1086-1094Publisher
ELSEVIER SCIENCE INC
DOI: 10.1002/jps.23433
Keywords
adenine-induced CRF; distribution; elimination; kidney uptake clearance; pharmacokinetics; transport; transporters
Funding
- Japan Society for the Promotion of Science (JSPS) [23790168]
- Grants-in-Aid for Scientific Research [23790168] Funding Source: KAKEN
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Chronic renal failure (CRF) leads to decreased drug renal clearance and glomerular filtration rate. However, little is known about renal tubular excretion and reabsorption in CRF. We examined transport activity of renal transporters using rats with adenine-induced CRF. We examined the effect of adenine-induced CRF on mRNA level, protein expression of transporters expressed in kidney by real-time polymerase chain reaction, and western blotting. In vivo kidney uptake clearances of benzylpenicillin and metformin, which are typical substrates for renal organic anion transporters Oat1 and Oat3 and organic cation transporters Oct1 and Oct2, respectively, were evaluated. Protein and mRNA expression levels of Oat1, Oat 3, Oct1, and Oct2 were significantly decreased in adenine-induced CRF rats. On the contrary, levels of P-glycoprotein and Mdr1b mRNA were significantly increased in adenine-induced CRF rats. The mRNA expression levels of Oatp4c1, Mate1, Urat1, Octn2, and Pept1 were significantly decreased. Kidney uptake clearance of benzylpenicillin and that of metformin were significantly decreased in adenine-induced CRF rats. Also, serum from CRF rats did not affect Oat1, Oat3, Oct1, and Oct2 function. In conclusion, our results indicate that adenine-induced CRF affects renal tubular handling of drugs, especially substrates of Oat1, Oat3, Oct1, and Oct2. (c) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:10861094, 2013
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