Impact of Polymorphisms of OAT1, OAT3, and OCT2 on Transportation of Potential Nephrotoxic Drugs

This study has been completed.
Sponsor:
Collaborator:
Department of Health, Executive Yuan, R.O.C. (Taiwan)
Information provided by (Responsible Party):
National Taiwan University Hospital
ClinicalTrials.gov Identifier:
NCT00251017
First received: November 8, 2005
Last updated: December 25, 2012
Last verified: December 2012
  Purpose

Transporters in kidney are critical in detoxification and elimination of xenobiotics from systemic circulation, and thus are major determinants of drug response and sensitivity. Transporters in the renal epithelium control the exposure of renal cells to nephrotoxic drugs and environmental toxins and thus determine xenobiotic-induced nephrotoxicity. Organic anion transporters (OATs) and organic cation transporters (OCTs) are two major classes of secretory transporters in the mammalian kidney. Among the uptake transporters, OAT1, OAT3, or OCT2 appear to be particularly important in the renal basolateral membrane to transport a large variety of endogenous and therapeutic compounds.

Recently, rapid advances in single nucleotide polymorphisms (SNPs) mapping can now be applied to characterize the individual patients who suffer adverse effects to a drug, or those for whom a drug shows efficacy. The aim of this study was to identify and functionally characterize OCT2 variants as a first step towards understanding whether genetic variation in OCT2 may contribute to interindividual differences in renal elimination of vancomycin. Taiwanese patients will be screened and 12 coding region variants of OCT2 will be identified. The non-synonymous variants of OAT1, OAT3, or OCT2 will then be constructed and characterized using in vitro human renal cell models. It is to establish whether genetic variants in OAT1, OAT3, or OCT2 are likely significant contributors to intersubject variability in drug response. In addition, approaches toward prevention of some drug-induced nephrotoxicity are discussed, based on molecular mechanisms of renal accumulation of these drugs. Perhaps the researchers' understanding of OAT1, OAT3, or OCT2 in pharmacogenomics may contribute to the goal of individualized drug therapy. Development of new strategies based on the understanding of their cellular handing may achieve safer and more effective therapy for personalized medicines.


Condition Intervention
Adverse Effects
Procedure: Vancomycin
Procedure: DNA are extracted from the whole blood of subjects

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Impact of Polymorphisms of OAT1, OAT3, and OCT2 on Transportation of Potential Nephrotoxic Drugs

Resource links provided by NLM:


Further study details as provided by National Taiwan University Hospital:

Primary Outcome Measures:
  • Single nucleotide polymorphism (SNP), plasma creatinine and vancomycin concentration [ Time Frame: 0, 2 hour after Vancomycin administration ] [ Designated as safety issue: No ]

Enrollment: 34
Study Start Date: July 2005
Study Completion Date: June 2006
Primary Completion Date: June 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Vancomycin
Effects of OCT2 genetic variation in renal elimination of Vancomycin
Procedure: Vancomycin
Two hour creatinine clearance before and after vancomycin
Procedure: DNA are extracted from the whole blood of subjects

Detailed Description:

Beta-lactam antibiotics, aminoglycosides, amphotericin B, cyclosporine, nonsteroidal anti-inflammatory drugs, antineoplastic, or antivirus drugs that are used extensively in clinical settings bear the risk of nephrotoxicity. This side effect is dose-dependent and has been attributed mainly to the accumulation of drugs in the renal proximal tubule. When assessing nephrotoxicity, both the dosage and the tubular secretion system, which allows transport of drug from blood to urine via the tubular cells, are important factors. This study was designed to investigate how renal transporters work in the renal secretion of specific drugs.

Transporters in kidney are critical in detoxification and elimination of xenobiotics from systemic circulation, and thus are major determinants of drug response and sensitivity. Transporters in the renal epithelium control the exposure of renal cells to nephrotoxic drugs and environmental toxins and thus determine xenobiotic-induced nephrotoxicity. Organic anion transporters (OATs) and organic cation transporters (OCTs) are two major classes of secretory transporters in the mammalian kidney. Among the uptake transporters, OAT1, OAT3, or OCT2 appear to be particularly important in the renal basolateral membrane to transport a large variety of endogenous and therapeutic compounds.

Recently, rapid advances in single nucleotide polymorphisms (SNPs) mapping can now be applied to characterize the individual patients who suffer adverse effects to a drug, or those for whom a drug shows efficacy. The aim of this study was to identify and functionally characterize OCT2 variants as a first step towards understanding whether genetic variation in OCT2 may contribute to interindividual differences in renal elimination of vancomycin. Taiwanese patients will be screened and 12 coding region variants of OCT2 will be identified. The non-synonymous variants of OAT1, OAT3, or OCT2 will then be constructed and characterized using in vitro human renal cell models. It is to establish whether genetic variants in OAT1, OAT3, or OCT2 are likely significant contributors to intersubject variability in drug response. In addition, approaches toward the prevention of some drug-induced nephrotoxicity are discussed, base on molecular mechanisms of renal accumulation of these drugs. Perhaps our understanding of OAT1, OAT3, or OCT2 in pharmacogenomics may contribute to the goal of individualized drug therapy. Development of new strategies based on the understanding of their cellular handing may achieve safer and more effective therapy for personalized medicines.

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects 16 years of age or older, of either sex.
  • Subjects have a medication including vancomycin
  • Subjects have realistic expectations of the benefit and limitation of the augmentation procedure, as determined by a willingness to sign the informed consent form after it has been carefully explained.

Exclusion Criteria:

  • Subjects have a medical condition that increased the risks of study participation (including pregnancy and poor renal function)
  • Subjects are taking medications (nephrotoxicants) that could confound study results.
  • Subjects presenting with history of autoimmune disorder, septic shock, or multiple organ failure.
  • Subjects with renal failure undergoing dialysis (hemodialysis [HD] or continuous ambulatory peritoneal dialysis [CAPD]), continuous venovenous hemofiltration (CVVH), or continuous arteriovenous hemodiafiltration (CAVHDF).
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00251017

Locations
Taiwan
Department of Surgery, National Taiwan University Hospital
Taipei, Taiwan, 100
Sponsors and Collaborators
National Taiwan University Hospital
Department of Health, Executive Yuan, R.O.C. (Taiwan)
Investigators
Study Chair: Ji-Wang Chern, Ph.D. National Taiwan University
Principal Investigator: Wen-Je Ko, M.D, Ph.D National Taiwan University Hospital
Principal Investigator: Fe-Lin Lin, Ph.D. National of University
Study Director: Chiung-Hua Huang, M.S National Taiwan University
  More Information

No publications provided

Responsible Party: National Taiwan University Hospital
ClinicalTrials.gov Identifier: NCT00251017     History of Changes
Other Study ID Numbers: 9361701301, DOH94-td-d-113-035(2)
Study First Received: November 8, 2005
Last Updated: December 25, 2012
Health Authority: Taiwan: Department of Health

Keywords provided by National Taiwan University Hospital:
single nucleotide polymorphisms (SNPs)
personalized medicines
Subjects 16 years of age or older, of either sex.
Subjects have a medication including vancomycin

Additional relevant MeSH terms:
Vancomycin
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 19, 2014