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Abstract: PO2363

Effect of Kidney Disease and Vitamin D Repletion on Drug Transporter Activity

Session Information

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

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Casal, Morgan Alexandra, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, United States
  • Prebehalla, Linda, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, United States
  • West, Raymond E., University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, United States
  • Shah, Nirav A., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Chonchol, Michel, University of Colorado School of Medicine, Aurora, Colorado, United States
  • Joy, Melanie S., University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, United States
  • Nolin, Thomas D., University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, United States
Background

CKD patients exhibit altered nonrenal drug clearance, which is reflected in numerous drug metabolism and transport pathways. Vitamin D (VitD) deficiency is common in CKD, and VitD-mediated regulation has been implicated in altering functional expression of renal and nonrenal transporters. This study aimed to elucidate the impact of VitD status (deficiency vs repletion) on drug transporter activity in CKD patients and healthy controls (HC).

Methods

VitD deficient (25[OH]D3 < 30 ng/mL) subjects with CKD stage I-III (n=15), CKD stage IV-V (n=8) and HC (n=9) were enrolled. The phenotypic probe drugs fexofenadine (FEX) and olmesartan (OLM) were used to assess P-glycoprotein (P-gp), organic anion transporter (OAT) and organic anion-transporting polypeptide (OATP) function, and endogenous N-methylnicotinamide (NMN) was used to assess multidrug and toxin extrusion proteins 1 and 2K (MATE1/2K) activity. FEX 60 mg and OLM 10 mg were orally administered at baseline (VitD deficiency) and after 12 weeks of oral therapy with VitD3 5000 IU daily and confirmed repletion (25[OH]D3 < 30 ng/mL). Serial blood and urine samples were collected for 48 hours. FEX, OLM, and NMN concentrations in plasma and urine were determined by LC/MS/MS and noncompartmental pharmacokinetic (PK) parameters were calculated.

Results

CKD IV-V subjects had 77% higher FEX systemic exposure (AUC, p=0.03), 37% lower clearance (p=0.03), and 68% longer half-life (p=0.0005) than HC at the time of VitD deficiency. In CKD I-III subjects, FEX AUC and Cmax were increased 28% (p=0.03) and 52% (p=0.004), respectively, after VitD repletion. No differences in OLM PK were observed between VitD phases or subject groups. CKD IV-V subjects exhibited a doubling of AUC0-12 and 50% decrease in renal clearance of NMN after VitD repletion, but no differences were statistically significant.

Conclusion

The FEX data suggest that nonrenal transporter function (likely intestinal P-gp and/or hepatic OATP) is decreased in VitD deficient CKD patients and may be improved by VitD repletion. Reasons for unchanged OLM PK likely relate to overlapping substrate specificity with other transporters that are minimally effected by CKD or VitD status. Conversely, NMN results may suggest that MATE1/2-K function is decreased by VitD.

Funding

  • Other NIH Support