Meta-analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression.
OBJECTIVE
Studies revealing conflicting results of the functional significance of MDR1 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 MDR1.


METHODS
Meta-analysis was performed on data from published studies investigating the influence of MDR1 C3435T SNP on digoxin pharmacokinetics, as well as MDR1 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 MDR1 mRNA expression and P-gp expression in the absence of digoxin administration.


RESULTS
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(0-4 h) or AUC(0-24 h) although C(max) 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 MDR1 mRNA or protein expression.


CONCLUSIONS
Our meta-analysis of available studies indicates that the synonymous MDR1 C3435T SNP does not affect the pharmacokinetics of digoxin and the expression of MDR1 mRNA. Future studies should focus on the impact of MDR1 haplotypes on the pharmacokinetics of MDR1 substrates rather than the C3435T SNP alone.
Chowbay
Balram
B
Laboratory of Clinical Pharmacology, Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore. ctebal@nccs.com.sg
Li
Huihua
H
David
Machin
M
Cheung
Yin Bun
YB
Lee
Edmund J D
EJ
D000284:Administration, Oral; D019540:Area Under Curve; D004077:Digoxin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005786:Gene Expression Regulation / Q000235:genetics; D019450:Genes, MDR / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007564:Japan / Q000208:ethnology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D044465:White People / Q000208:ethnology
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D004077:Digoxin