Abstract: SA-PO652

Effect of CKD on Expression of Cyp3a11, Cyp2c37, Cyp2d22, and Oatp1b2 in C57BL/6 Mice

Session Information

Category: Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

  • 1601 Pharmacokinetics, Pharmacodynamics, Pharmacogenomics

Authors

  • Tonial, Nicholas, Western University, London, Ontario, Canada
  • Hartjes, Emily D., Western University, London, Ontario, Canada
  • Thibodeau, Jean-Francois, ProMetic BioSciences Inc., Laval, Quebec, Canada
  • Holterman, Chet E., Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • Kamto, Eldjonai, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • Gagnon, Lyne, ProMetic BioSciences Inc., Laval, Quebec, Canada
  • Urquhart, Brad, Western University, London, Ontario, Canada
Background

Drug disposition can be severely altered in patients with chronic kidney disease (CKD) due to the multitude of physiological changes that occur. Cytochrome P450s and membrane transporters are major contributors to overall drug disposition, and have been extensively studied in rodent models of CKD. Induction of CKD in rat models by 5/6 nephrectomy or dietary treatment with adenine have shown decreased expression of CYPs such as CYP3A2 and CYP2C11. CKD mouse models using 3/4 nephrectomy have also shown a reduced expression of Cyp3a11. However, the use of adenine to induce CKD in mice for the purpose of evaluating drug response has not been studied. This study investigated the effects of adenine-induced CKD in C57BL/6 mice on the expression of Cyp3a11, Cyp2c37, Cyp2d22, and Oatp1b2. It was hypothesized that CKD would decrease the expression of these genes.

Methods

C57BL/6 mice were fed standard chow (n=4) or standard chow supplemented with 0.25% adenine (n=6) for 4 weeks. Mice were sacrificed, organs collected and RNA was isolated and analyzed by RT-qPCR for Cyp3a11, Cyp2c37, Cyp2d22, and Oatp1b2 with expression levels normalized to beta actin using the ΔΔCT method.

Results

Plasma urea and creatinine were significantly elevated (p<0.05, p<0.01 respectively), and creatinine clearance was significantly reduced (p<0.01) in adenine-fed mice compared to controls. No differences were found between the two groups for the four genes analyzed (p>0.05), however a trend was observed for increased Cyp2c37 expression in CKD mice compared to control mice (143.5% increase; p=0.0967).

Conclusion

CKD did not alter expression levels of Cyp3a11, Cyp2c37, Cyp2d22, and Oatp1b2 in C57BL/6 mice. Although not a statistically significant increase, Cyp2c37 expression remains of interest for future studies to better elucidate this change. Analysis of protein expression and functional activity remain to be determined to better understand the impact of CKD on drug metabolism and distribution in this mouse model.