Kidney Week

Abstract: PO0319

Influence of Vitamin D and Uremia on Functional Expression of Drug Transporters in Human Proximal Tubule Cells

Session Information

• Bone and Mineral Metabolism: Basic
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 401 Bone and Mineral Metabolism: Basic

Authors

• Tuey, Stacey M., University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, United States

Stacey M. Tuey,

• Nolin, Thomas D., University of Pittsburgh, Department of Pharmacy & Therapeutics, Pittsburgh, Pennsylvania, United States

Thomas D. Nolin,

• Joy, Melanie S., University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, United States

Melanie S. Joy,

Background

Vitamin D (VitD) deficiency is common in patients with chronic kidney disease (CKD), with prevalence rates as high as 90%. CKD and VitD have independently been shown to modulate the function and expression of various drug transporters, potentiating drug-drug interactions and pharmacokinetic alterations. However, it remains unclear how the combination of CKD and VitD alters drug transporters. The purpose of this study was to evaluate the function and expression of drug transporters in human proximal tubule cells (hPTCs) following treatment with VitD analogues under in vitro conditions employing human healthy serum (HS) and uremic serum (US) to mimic the CKD environment.

Methods

hPTCs were exposed to 10% HS or 10% US for 24 h, followed by treatment with cholecalciferol (D₃) or the active form, calcitriol (1,25D₃) at 100 or 240 nM concentrations or 2% ethanol vehicle control (VEH) for 6 days. RT-qPCR and immunoblotting were used to assess effects on gene and protein expression, respectively of P-gp (efflux) and OATP4C1 (uptake) transporters. Apical to basolateral (A->B) and basolateral to apical (B->A) transport was assessed in hPTCs using transwell inserts and the transporter probe [³H]Digoxin (DIG).

Results

Data are shown in the Table. Compared to VEH, 1,25D₃ increased P-gp gene expression under HS and US (with exception of the 240 nM concentration). 1,25D₃ also increased SLCO4C1 protein in HS, but no increase was demonstrated in US. B->A transport was enhanced in HS under treatment with 1,25D₃.

Conclusion

These data suggest that uremia decreases OATP4C1 expression and prevents an induction of OATP4C1 expression and function by 1,25D₃. Enhanced B->A transport in HS under treatment with 1,25D₃ was consistent with the up-regulation of P-gp and SLCO4C1. These alterations may help to inform disposition of transporter substrates under VitD treatments.

Funding

• Other NIH Support