Effect of, OAT3, on the Renal Secretion of Cefotaxime
Condition: Focus Groups
Study type: Interventional
Phase: Phase 1

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.

      In recent studies, we identified nine non-synonymous OAT3 variants among subjects
      participating in the SOPHIE study. We cloned and introduced each variant into a heterologous
      expression system and tested the encoded transporters for their ability to transport estrone
      sulfate (a documented substrate for OAT3). Four variants were identified that resulted in a
      complete loss of function: F129L (in one Hispanic subject), R149S (in an Caucasian and an
      African American subject), Q239stop (in the same African American subject), and R277W (in an
      Asian subject). In the subject with two non-functional variants, it is unknown whether the
      variants occur on the same chromosome, or if the variants are on different chromosomes. The
      latter would potentially make the subject completely OAT3 deficient. An additional variant
      (I305F) which showed reduced transport ability for some, but not all, OAT3 substrates was
      identified in three Asian and one Hispanic subject. One variant (A310V) which showed
      increased transport of estrone sulfate compared to the common allele was identified in a
      single Caucasian subject.

      This study will address the following question: Do individuals who carry altered-function in
      OAT3 and related variants exhibit differences in the pharmacokinetics of cefotaxime in
      comparison to individuals who carry the common allele?
    

Intervention name(s): Cefotaxime
Intervention type(s): Drug
Intervention description(s): Cefotaxime will be administered as a single IV push of 2 grams over 5 minutes.
Other intervention name(s): Claforan; Cefotaxime Sodium
Intervention MeSH terms: Cefotaxime; Cefoxitin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Health Services Research
Keywords: Healthy volunteers willing to be dosed with cefotaxime