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Abstract: SA-PO640

Effect of CKD on Fexofenadine Disposition in Humanized OATP1B1/1B3 Mice

Session Information

  • Pharmacology
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1700 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Tonial, Nicholas, Western University, London, Ontario, Canada
  • Lim, Yong Jin (James), Western University, London, Ontario, Canada
  • Urquhart, Brad, Western University, London, Ontario, Canada
Background

Patients with chronic kidney disease (CKD) often experience variable responses to drug therapies evidenced by their elevated incidence of adverse drug reactions. Cytochrome P450s (CYPs) and drug transporters are major contributors to drug disposition, as they mediate drug metabolism and removal from blood, respectively, to facilitate non-renal excretion. Rodent models of CKD exhibit reduced CYP expression and activity. However, the impact of CKD on drug transporters, namely organic anion transporting polypeptides (OATPs), is not well elucidated. Fexofenadine is a commonly used transporter probe ideal to study non-renal clearance since it is not metabolized and not eliminated in the urine. Multiple studies have documented significantly increased fexofenadine exposure in CKD patients, although the mechanism is unclear. This study investigated the effects of CKD on hepatic drug transporter activity in a humanized hepatic OATP1B1/1B3 mouse model by evaluating the liver distribution fexofenadine. It was hypothesized that CKD would decrease the activity of these transporters, as shown by a reduction in hepatic fexofenadine distribution.

Methods

CKD was induced in humanized OATP1B1 and OATP1B3 FVB/N mice by feeding chow supplemented with 0.2% adenine (n=6) for a total of 28 days while controls (n=6) received standard chow. Blood and organs were collected at sacrifice and plasma creatinine concentrations and the liver to plasma ratio of fexofenadine (L:PFEX) were measured using ultra performance liquid chromatography coupled to mass spectrometry.

Results

Plasma creatinine was two-fold higher in adenine-fed mice compared to controls (p=0.0011).L:PFEXwas reduced by 15%, indicating a modest decrease in hepatic fexofenadine liver distribution (p=0.1870).

Conclusion

Induction of CKD did not significantly alter the liver distribution of fexofenadine in the humanized hepatic OATP1B1/1B3 mouse model. Further analysis into expression levels of these transporters, and other hepatic transporters such as P-glycoprotein, will provide further insight into the impact of CKD on drug transporters and distribution of fexofenadine in the liver.

Funding

  • Government Support - Non-U.S.