Renal Uptake of Substrates for Organic Anion Transporters Oat1 and Oat3 and Organic Cation Transporters Oct1 and Oct2 is Altered in Rats with Adenine-Induced Chronic Renal Failure

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ABSTRACT

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. © 20l2 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1086-1094, 2013

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INTRODUCTION

All patients with glomerular filtration rate (GFR) of less than 60 mL/min per l.73 m2 for 3 months or more are classified as having chronic kidney disease (CKD), regardless of the presence or absence of kidney damage.-1 The number of patients with CKD has been rapidly increasing over the past few decades. Furthermore, end-stage renal disease and chronic renal failure (CRF) can results in the requirement of dialysis and in decay of the quality of life, but CKD is curable in an early stage. Early

Materials

Benzylpenicillin was purchased from Wako (Osaka, Japan), and metformin was obtained from Alexis (Lausen, Switzerland). A primary antibody specific for Oatl and Oat3 was purchased from Cosmo Bio (Tokyo, Japan), Oct2 and P-glycoprotein were from Santa Cruz Biotechnology (Santa Cruz, California), Octl and Mrp2 were from AbcamLid (Cambridge, UK), and Bcrp was from Santa Cruz Biotechnology. All other chemicals and reagents were commercially available and of the highest purity possible.

Animal Experiments

Male Wistar

Biochemical Parameters and Body Weight in Normal and Adenine-Induced CRF Rats

Biochemical parameters and body weights in the two groups of rats were shown in Table 2. Compared with normal rats, adenine-induced CRF rats had high levels of serum creatinine and BUN. On the contrary, body weight and GFR of adenine-induced CRF rats was less than that of normal rats. These results correspond to the results of a previous study.19

mRNA Expression of Kidney Transporters in Adenine-Induced CRF Rats

Figure 1 shows the levels of mRNAs coding for kidney transporters. The mRNA levels of Oat1, Oat3, Oatp4c1, Oct1, Oct2, Mate1, Octn2, Urat1, and Pept1

DISCUSSION

The number of patients with CKD is increasing year by year. Because CKD is commonly associated with lifestyle diseases such as obesity, hypertension, and diabetes, patients often need to take various medicines. CRF, which was final clinical condition of CKD, involves the various metabolic abnormalities including azotemia, abnormal urea cycle, abnormal pattern of free amino acids, abnormal electrolyte metabolism, hyperlipidemia, hormonal abnormalities, and reduced glucose tolerance.16., 17., 18.

CONCLUSIONS

Our results showed that renal uptakes of substrates for Oat1, Oat3, Oct1, and Oct2 are decreased in adenine-induced CRF rats. These changes were caused by a decrease in expression levels of Oat1, Oat3, Oct1, and Oct2 in adenine-induced CRF rats. For safe drug treatment in CRF patients, it might be important to consider the kidney transporter function in addition to GRF.

ACKNOWLEDGMENTS

This work was in part supported by Japan Society for the Promotion of Science (JSPS) KAKENHI grant number 23790168.

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