Impact of Polymorphisms of OAT1, OAT3, and OCT2 on Transportation of Potential Nephrotoxic Drugs
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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 |
- 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 |
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| Taiwan | |
| Department of Surgery, National Taiwan University Hospital | |
| Taipei, Taiwan, 100 | |
| 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 May 22, 2013