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

This study is not yet open for patient recruitment.
Verified by National Taiwan University Hospital November 2005

Sponsors and Collaborators: National Taiwan University Hospital
Department of Health
Information provided by: National Taiwan University Hospital
ClinicalTrials.gov Identifier: NCT00251017

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 secretary 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 in vitro human renal cells models. It is to establish whether genetic variants in OAT1, OAT3 or OCT2 are likely significant contributor to intersubject variability in drug response. In addition, approaches toward prevention of some drugs-induced nephrotoxicity are discussed, base on molecular mechanisms of renal accumulation of these drugs. Perhaps our understandings 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
Subjects 16 Years of Age or Older, of Either Sex.
Subjects Have a Medication Including Vancomycin
 Procedure: Two hour creatinine clearance before and after vancomycin
 Procedure: DNA are extracted from the whole blood of subjects

MedlinePlus consumer health information 

Study Type: Interventional
Study Design: Prevention, Non-Randomized, Open Label, Active Control, Single Group Assignment, Safety/Efficacy Study

Further study details as provided by National Taiwan University Hospital:
Primary Outcomes: single nucleotide polymorphism, renal function, vancomycin concentration
Secondary Outcomes: single nucleotide polymorphism, renal function, vancomycin concentration
Expected Total Enrollment:  200

Study start: November 2005;  Expected completion: June 2006
Last follow-up: June 2006;  Data entry closure: June 2006

Beta-lactams 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 accumulation of drug in renal proximal tubule. When assessing nephrotoxicity, both 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 secretary 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 in vitro human renal cells models. It is to establish whether genetic variants in OAT1, OAT3 or OCT2 are likely significant contributor to intersubject variability in drug response. In addition, approaches toward prevention of some drugs-induced nephrotoxicity are discussed, base on molecular mechanisms of renal accumulation of these drugs. Perhaps our understandings 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 above,  Genders Eligible for Study:  Both
Criteria

Inclusion Criteria:

- i. Subjects 16 years of age or older, of either sex. ii. Subjects have a medication including vancomycin iii. 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:

- i. Subjects have a medical condition that increased the risks of study participation (including pregnancy and poor renal functional) ii. Subjects are taking medications (nephrotoxicants) that could confound study results.

iii. Subjects presenting with history of autoimmune disorder, septic shock, or multiple organ failure.

iv. Subjects are with renal failure undergoing dialysis (HD, or CAPD), CVVH, or CAVHDF.

Location and Contact Information

Please refer to this study by ClinicalTrials.gov identifier  NCT00251017

Wen-Je Ko, M.D.,Ph.D.      886-2-23123456  Ext. 3098    wenje@ha.mc.ntu.edu.tw
Chiung-Hua Huang, M.S      886-23123456  Ext. 8389    d93423004@ntu.edu.tw

Taiwan
      Department of Surgery, National Taiwan University Hospital, Taipei,  100,  Taiwan
Wen-Je Ko, M.D., Ph.D  886-2-23123456  Ext. 3098    wenje@ha.mc.ntu.edu.tw 
Chiung-Hua Huang, M.S  886-23123456  Ext. 8389    d93423004@ntu.edu.tw 
Wen-Je Ko, M.D, Ph.D.,  Principal Investigator
Ji-Wang Chern, Ph.D.,  Principal Investigator
Fe-Lin Lin, Ph.D.,  Sub-Investigator
Chiung-Hua Huang,  Sub-Investigator

Study chairs or principal investigators

Ji-Wang Chern, Ph.D.,  Study Chair,  National Taiwan University   
Wen-Je Ko, M.D, Ph.D,  Principal Investigator,  National Taiwan University Hospital   
Fe-Lin Lin, Ph.D.,  Principal Investigator,  National of University   
Chiung-Hua Huang, M.S,  Study Director,  National Taiwan University   

More Information

Study ID Numbers:  9361701301; DOH94-td-d-113-035(2)
Last Updated:  December 8, 2005
Record first received:  November 8, 2005
ClinicalTrials.gov Identifier:  NCT00251017
Health Authority: Taiwan: Department of Health
ClinicalTrials.gov processed this record on 2006-01-10

Resources




Common Treatments

[ Disclaimer: The information on GoldBamboo for any particular treatment, medicine, drug, or herbal product might be missing or incomplete, and should never be used as a single source of knowledge. GoldBamboo generally has links to authoritative sites displayed toward the bottom of each topic page under the heading "Resources". ]

Follow Us