Evaluation of Renal Drug Transport in Healthy Volunteers
Condition: Kidney Disease
MeSH terms: Kidney Diseases
Study type: Interventional

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.
    

Detailed description: 
      The purpose of this study is to measure GFR (using iothalamate clearance) and renal tubular
      function (using PAH clearance) in healthy subjects. The protocol will be approved by the
      University of Maryland IRB and the General Clinical Research Center (GCRC) advisory committee
      (GAC). Following the informed consent process, each subject will be evaluated for past
      medical history, undergo a physical examination and routine laboratory tests (including
      urinary protein:creatinine ratio) conducted within 1 month prior to the study visit.

      Day 1: Vital signs (heart rate, blood pressure, respiratory rate) will be recorded hourly
      throughout each study visit. Subjects will have intravenous catheters inserted into forearm
      veins of each arm for blood collection and intravenous infusion iothalamate and PAH. From 30
      minutes before marker administration until the end of each evaluation period, subjects will
      remain in a semireclined position except during urine collections. A constant-rate infusion
      will then be initiated at 1 mL/min for a total of 3 hours, with the concentration in the
      infusate determined based on the patient's estimated renal clearance and target plasma
      concentration of 10 mg/L and 15 mg/L for iothalamate, and PAH, respectively. Day 2: Washout
      Day 3: Subject will begin taking probenecid. Day 4 (Study visit #2): Subject will be admitted
      to the GCRC at 8AM. The final dose of probenecid will be administered. The renal function
      test will then be conducted as described for study visit #1 above. Day 11: Subject will be
      contacted for monitoring of adverse events according to GCRC procedures.
    

Intervention name(s): probenecid
Intervention type(s): Drug
Intervention description(s): 500 mg q 6 hrs
Intervention MeSH terms: Probenecid
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: OAT; GFR; renal function; PAH