Pharmacokinetic Significance of Renal OAT3 (SLC22A8) for Anionic Drug Elimination in Patients with Mesangial Proliferative Glomerulonephritis
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Our previous studies showed that the mRNA level of human organic anion transporter (hOAT) 3 in the kidney was correlated with the rate of elimination of an anionic antibiotic cefazolin. However, the correlation coefficient was not so high. In the present study, therefore, we enrolled more patients to examine whether additional factors were responsible for the correlation.
hOAT mRNA levels in renal biopsy specimens were quantified using the real-time polymerase chain reaction method. The elimination rates for the free fraction of cefazolin were determined in patients with various renal diseases.
In the present study, the coefficient of correlation between the hOAT3 mRNA level and the elimination rates for the free fraction of cefazolin was not so high in the patients overall as in our previous study (r = 0.536). However, following the classification of renal diseases, a better correlation was obtained in patients with mesangial proliferative glomerulonephritis (r = 0.723). In contrast, multiple regression analyses including gender, age, and liver function did not result in any improvements in the correlation coefficients.
These results suggest that the hOAT3 mRNA level is a significant marker of pharmacokinetics with which to predict the rate of elimination of cefazolin in patients with mesangial proliferative glomerulonephritis.
Key Wordsorganic anion transporter human kidney renal diseases real-time PCR renal clearance
This work was supported by a grant-in-aid for Comprehensive Research on Aging and Health from the Ministry ofHealth and Welfare of Japan (H15-Choju-006), by a grant-in-aid for Scientific Research from the Ministry of Education,Culture, Sports, Science, and Technology of Japan, by agrant-in-aid from the Japan Research Foundation for Clinical Pharmacology, and by the 21st Century COE program“KnowledgeInformation Infrastructure for Genome Science.”
- 7.Inui, K., Okuda, M. 1998Cellular and molecular mechanisms of renal tubular secretion of organic anions and cationsClin. Exp. Nephrol.2100108Google Scholar
- 9.Burckhardt, B. C., Burckhardt, G. 2003Transport of organic anions across the basolateral membrane of proximal tubule cellsRev. Physiol., Biochem. Pharmacol.14695158Google Scholar
- 10.Sakurai, Y., Motohashi, H., Ueo, H., Masuda, S., Saito, H., Okuda, M., Mori, N., Matsuura, M., Doi, T., Fukatsu, A., Ogawa, O., Inui, K. 2004Expression levels of renal organic anion transporters (OATs) and their correlation with anionic drug excretion in patients with renal diseasesPharm. Res.216167PubMedGoogle Scholar
- 21.S. Soodvilai, S. H. Wright, W. H. Dantzler, V. Chatsudthipong. Involvement of tyrosine kinase and PI3K in the regulation ofOAT3-mediated estrone sulfate transport in isolated rabbit renal proximal tubules. Am. J. Physiol. Renal. Physiol. in press.Google Scholar
- 28.Nishizato, Y., Ieiri, I., Suzuki, H., Kimura, M., Kawabata, K., Hirota, T., Takane, H., Irie, S., Kusuhara, H., Urasaki, Y., Urae, A., Higuchi, S., Otsubo, K., Sugiyama, Y. 2003Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokineticsClin. Pharmacol. Ther.73554565PubMedCrossRefGoogle Scholar
- 29.Niemi, M., Schaeffeler, E., Lang, T., Fromm, M. F., Neuvonen, M., Kyrklund, C., Backman, J. T., Kerb, R., Schwab, M., Neuvonen, P. J., Eichelbaum, M., Kivisto, K. T. 2004High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1)Pharmacogenetics14429440PubMedGoogle Scholar