This proposal focuses on the role of vitamin D as a modulator of xenobiotic clearance in patients with chronic kidney disease (CKD). Vitamin D can influence the regulation of genes responsible for metabolism and transport processes that mediate xenobiotic clearance. This is highly relevant since vitamin D treatment is common, as deficiency (total 25(OH)D level <30 ng/mL) is observed in up to 90% of CKD cohorts. Previous published research by the Principal Investigators and others has shown that renal and nonrenal xenobiotic clearance pathways mediated by cytochrome P450 (CYP) enzymes and transporters is altered in CKD. Given the 24 M US citizens with CKD are prescribed an average of 10-12 different medications daily, the clinical realities of altered xenobiotic clearance in CKD (drug interactions, side effects, altered efficacy, and confusion for clinicians prescribing and/or monitoring treatments) are not trivial. Importantly, increasing evidence indicates that vitamin D deficiency is a significant non-traditional cardiovascular risk factor, and vitamin D is important or bone and musculoskeletal health, kidney protection, cancer prevention, and decreased severity or risk of autoimmune and infectious diseases. In this proposal, we developed a translational study employing in vivo and in vitro studies to investigate how vitamin D alters the activity of drug metabolism and transport pathways in CKD. We propose to characterize the in vivo activity of xenobiotic metabolism and transport pathways in CKD patients and healthy controls under the opposing influences of vitamin D deficiency and repletion. Moreover, physiologically-based pharmacokinetic models will explore mechanisms for vitamin D and uremia on variations in drug metabolism and transport using data derived from the planned in vivo and in vitro studies. Our central hypothesis is that vitamin D status independently affects metabolism and transport function in CKD patients. An over-arching goal of this proposal is to make drug therapies safer and more effective to reduce the significant morbidity and mortality in patients with CKD. Three independent Specific Aims comprised of in vivo and in vitro studies were formulated to address the key hypotheses: 1) The in vivo function of individual pathways of xenobiotic metabolism and transport are affected by vitamin D status and by CKD, 2) CKD alters the activity of individual CYPs responsible for vitamin D metabolism, leading to modified pharmacokinetics of cholecalciferol, and 3) Vitamin D treatment and simulated CKD differentially alter the expression and function of drug metabolizing enzymes and transporters in kidney and liver cells. These studies will be central to determine where more scrutiny is warranted in evaluating clinical risks for drug interactions, altered efficacy and toxicity of therapies, and for guidance on appropriate vitamin D deficiency and maintenance regimens. Long term benefits of this research are improvements in medication management, drug dosing guidelines, and corresponding outcomes in targeted organs and/or diseases for vitamin D treated patients. The proposed research would have high impact through the public health benefit of improving care provided to CKD patients, serving as a basis for future study of alterations in drug metabolism and transport, and provision of much needed information on vitamin D metabolism and pharmacokinetics in CKD.

R01GM107122

2014-09-15

2020-08-31