Ignite Creation Date:
2024-05-05 @ 11:57 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00187655
Status:
COMPLETED
Last Update Posted:
2014-10-29
First Post:
2005-09-13
Brief Title:
Effect of OAT3 on the Renal Secretion of Cefotaxime
Sponsor:
University of California San Francisco
Organization:
University of California San Francisco
Study Overview
Official Title:
Effect of Genetic Variation in the Transporter OAT3 on the Renal Secretion of Cefotaxime
Status:
COMPLETED
Status Verified Date:
2014-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 eg 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 ie 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 15 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
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 15 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None