Meta‐analysis of the influence of <i>MDR1</i> C3435T polymorphism on digoxin pharmacokinetics and <i>MDR1</i> gene expression

DOI Web Site Web Site 7 Citations

Abstract

<jats:sec><jats:title>Aims</jats:title><jats:p>Studies revealing conflicting results of the functional significance of <jats:italic>MDR1</jats:italic> exon 26 C3435T SNP on the disposition of digoxin in different ethnic groups led us to perform a meta‐analysis on published data investigating the influence of C3435T SNP on the pharmacokinetics of digoxin and the expression of <jats:italic>MDR1</jats:italic>.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Meta‐analysis was performed on data from published studies investigating the influence of <jats:italic>MDR1</jats:italic> C3435T SNP on digoxin pharmacokinetics, as well as <jats:italic>MDR1</jats:italic> expression in Caucasian and Japanese populations. The following outcomes were included: exposures to digoxin measured by area under the concentration–time curve and maximum concentration, the mean intestinal <jats:italic>MDR1</jats:italic> mRNA expression and P‐gp expression in the absence of digoxin administration.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The overall results of the meta‐analysis in Caucasian and Japanese subjects suggested no major influence of the C3435T SNP on exposure levels of digoxin as determined by AUC<jats:sub>0−4 h</jats:sub> or AUC<jats:sub>0−24 h</jats:sub> although <jats:italic>C</jats:italic><jats:sub><jats:italic>max</jats:italic></jats:sub> values for digoxin were lower in wild‐type (CC) subjects compared with subjects harbouring TT genotypes. Subgroup analysis by ethnic populations showed the oral availability of digoxin to be lower in wild‐type Caucasian populations compared with wild‐type Japanese subjects. No causal relationships were detected between the C3435T SNP and <jats:italic>MDR1</jats:italic> mRNA or protein expression.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our meta‐analysis of available studies indicates that the synonymous <jats:italic>MDR1</jats:italic> C3435T SNP does not affect the pharmacokinetics of digoxin and the expression of <jats:italic>MDR1</jats:italic> mRNA. Future studies should focus on the impact of <jats:italic>MDR1</jats:italic> haplotypes on the pharmacokinetics of <jats:italic>MDR1</jats:italic> substrates rather than the C3435T SNP alone.</jats:p></jats:sec>

Journal

Citations (7)*help

See more

Keywords

Report a problem

Back to top