Evaluation of Renal Drug Transport in Healthy Volunteers
Status:
Completed
Trial end date:
2007-06-01
Target enrollment:
Participant gender:
Summary
The process of drug elimination that occurs within the kidneys is complex, and involves
filtration, secretion and absorptive mechanisms. Many drugs, metabolites and toxins,
including organic anions and cations, rely on renal mechanisms for elimination from the body.
Failure to recognize the contribution of renal mechanisms involved in drug elimination during
the drug development process can result in drug interactions or toxicity in clinical trials.
This is increasingly important due to the use of OAT1 inhibitors such as probenecid that are
being used in adjuvant treatment regimens. Thus, in order to more fully understand the
effects renal disease, drugs and nephrotoxins on the renal transport pathways of tubular
secretion in humans, novel approaches that incorporate both in vitro (experimental) as well
as clinical observations (clinical trial), also called in-vitro/in-vivo correlations (IVIVC)
need to be developed. These methods can then be used to identify and evaluate specific kidney
"probe" drugs that undergo extensive tubular secretion. Such approaches are needed to
characterize drug clearance by tubular mechanisms and to identify potentially significant
drug-drug interactions prior to exposure to patients in Phase 2 and 3 clinical trials. This
investigator-initiated pilot project aims to determine the pharmacokinetics of selected
FDA-approved compounds (PAH, iothalamate) for use in IVIVC model development. The proposed
research is innovative, because it involves a translational approach to development of an
IVIVC model applied to renal drug clearance. It is our expectation that the resultant
approach will further our understanding of pharmacogenomics, inter-subject variability and
renal drug clearance. This approach will generate important new information regarding in
vitro drug-drug interactions in light of many new and potent OAT1 blocking agents being
introduced for the treatment of human diseases. In future studies, we hope to fully
characterize the effects of diseases such as diabetes, hypertension, and nephropathy on renal
drug transport mechanisms using IVIVC models. We expect that results from this NIH-funded
study will provide needed preliminary data to design future pharmacogenomic and drug
interaction studies in humans.
Phase:
N/A
Details
Lead Sponsor:
University of Maryland University of Maryland, Baltimore
Collaborators:
National Institute of General Medical Sciences (NIGMS) National Institutes of Health (NIH)