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Clinical Trials/NCT00187655
NCT00187655CompletedPhase 1

Effect of Genetic Variation in the Transporter, OAT3, on the Renal Secretion of Cefotaxime

University of California, San Francisco0 sites24 target enrollmentStarted: January 2004Last updated:
Conditions
Interventions
Drugs

Trial Snapshot

Phase
Phase 1
Status
Completed
Enrollment
24
Primary Endpoint
Effect of OAT3 on Renal Secretion of Cefotaxime IV Based on Genotype

Study Overview

Brief Summary

In the proposed study, we plan to use a genotype to phenotype strategy to study the role of the organic anion transporter, OAT3, in drug response. More specifically we will examine the contribution of OAT3 to the renal clearance of anionic drugs such as cefotaxime by studying individuals with a non-functional (or poorly-functional) variant of OAT3.

Detailed Description

Traditionally, clinical pharmacogenetic studies have begun with identifying a known phenotype (e.g., an aberrant response to a drug) followed by isolating the variant protein and gene responsible for that phenotype. With the sequence of most human genes known, it is possible to carry out pharmacogenetic studies in the reverse manner (i.e., genotype to phenotype). Patients with a known variant of a gene can be studied for their response to certain drugs, which can help elucidate the importance of that gene in drug response. In the proposed study, we plan to use a genotype to phenotype strategy to study the role of OAT3 and related variants in drug response.

Renal elimination of anionic drugs occurs by filtration and active secretion. For secretion, the drug is transported from the blood into the renal tubular cell through the basolateral membrane. This transport occurs against both a concentration and electrochemical gradient, and must therefore be mediated by organic anion transporters (OATs). To date, six human OATs have been identified, OAT 1-5, and OAT7. OAT1 and OAT3 are the dominant OATs found on the basolateral aspect of the renal proximal tubular cells and are hence suspected of playing a significant role in renal anionic drug elimination [3, 4].

Active renal tubular secretion of most beta-lactam antibiotics, including cephalosporins, has long been recognized, with OATs likely playing a major role, though the relative role of each is unclear [5]. In vivo studies have demonstrated that the cephalosporin cefotaxime has a ten-fold higher affinity for OAT3 than OAT1 [6]. Thus, patients with OAT3 variants would be expected to exhibit altered renal secretion of cefotaxime.

Cefotaxime is a common cephalosporin used in the treatment of bacterial infections. Dosed up to 1-2 mg every 6-8 hours, it has been shown to be safe in patients with normal renal function. Cefotaxime is given intravenously, and is metabolized to desacetyl cefotaxime (DACM) which retains antibacterial activity. DACM is further metabolized to two inactive metabolites, M2 and M3; all four forms of cefotaxime are renally eliminated, with active secretion representing a significant percentage of total clearance (44% for cefotaxime, 64% for DACM) [7]. The half-life of cefotaxime and DACM are 1 and 1.5 hours, respectively. Patients with poorly functional OAT3 and related variants might be expected to exhibit reduced tubular secretion of both cefotaxime and its metabolites, and result in higher or prolonged blood levels. Because such variants may reduce the amount of cefotaxime that enters the tubular cells, they may also be associated with a reduced incidence of cephalosporin-induced nephrotoxicity.

The PMT group has a collection of 500 DNA samples from young, healthy adults from four major ethnic groups (125 each from Caucasians, African-Americans, Mexicans, and Chinese). This collection (The Pharmacogenetics of Membrane Transporters), is referred to as "SOPHIE" (Study of Pharmacogenetics in Ethnically-diverse Populations), and includes only volunteers who have consented to be called back for consideration of enrollment in future studies.

Study Design

Study Type
Interventional
Allocation
Na
Intervention Model
Single Group
Primary Purpose
Health Services Research
Masking
None

Eligibility Criteria

Ages
18 Years to 45 Years (Adult)
Sex
All
Accepts Healthy Volunteers
Yes

Inclusion Criteria

  • Previous participation in the "SOPHIE" study;
  • Has a specific genotype for OAT3

Exclusion Criteria

  • Under 18 years old or over 45 years old;
  • Pregnant (pregnancy status in female subjects will be determined by a urine pregnancy test before study drug administration);
  • They report a prior history of any allergic reaction to cephalosporin antibiotic, or severe hypersensitivity to penicillin;
  • Has a prior history of renal or hepatic dysfunction (renal and hepatic function will also be determined for each subject with prescreening blood tests);
  • Taking a medication that could confound study results (such as known substrates or inhibitors of OATs);
  • They do not consent to participate in the study.

Arms & Interventions

Cefotaxime

Other

Cefotaxime will be administered as a single IV push of 2 grams over 5 minutes.

Intervention: Cefotaxime (Drug)

Outcomes

Primary Outcomes

Effect of OAT3 on Renal Secretion of Cefotaxime IV Based on Genotype

Time Frame: post dose up to 24 hours

Participants were stratified by their OCT3 genotype, heterozygous vs homozygous. The renal clearance of cefotaxime was measured by urine content of cefotaxime metabolites in participants after the single IV push administration of 2 grams of cefotaxime.

Secondary Outcomes

No secondary outcomes reported

Investigators

Sponsor Class
Other
Responsible Party
Sponsor

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