Polymorphisms of multidrug resistance gene (MDR1) and cyclosporine absorption in de novo renal transplant patients.
BACKGROUND
Several single nucleotide polymorphisms (SNPs) in the multidrug resistance (MDR1) gene may play a role in the interindividual variation of cyclosporine A (CsA) absorption in renal transplant patients.


METHODS
An analysis of CsA absorption measured by the dose- and weight-adjusted 4 hr area under the time-concentration curve, AUC(0-4)/mg doseCsA/kg, was conducted on day 3 after transplantation, in 69 de novo renal transplant patients who were genotyped for MDR1 SNPs. Follow-up pharmacogenomic analysis at 1 month posttransplant was performed utilizing dose- and weight-adjusted 2-hour postdose CsA concentration (C2).


RESULTS
AUC(0-4)/mg doseCsA/kg was significantly higher (P=0.024) in (C/C)3435 individuals than in a grouped population of (C/T)3435 and (T/T)3435 patients on postoperative day 3. G2677T variants were not significantly correlated with CsA absorption (P=0.084). The number of C3435-G2677 haplotypes was the best predictor of CsA exposure. At 1 month posttransplant, no correlation was seen between MDR1 SNPs and CsA exposure. The frequency of wild-type variants for C3435T and G2677T were 61% and 77.6%, respectively. SNPs at G2677T and C3435T loci were found to be in linkage disequilibrium.


CONCLUSIONS
MDR1 polymorphisms are associated with differences in CsA exposure only in the first posttransplant week.
Foote
Clary J
CJ
Department of Pathology, Queen Elizabeth II Health Sciences Centre/ Dalhousie University, Halifax, NS, Canada.
Greer
Wenda
W
Kiberd
Bryce
B
Fraser
Albert
A
Lawen
Joseph
J
Nashan
Bjorn
B
Belitsky
Philip
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D016572:Cyclosporine / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003596:Cytosine; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000502:physiology*; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013941:Thymine; D014019:Tissue Donors; D014184:Transplantation, Homologous
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003596:Cytosine; D004247:DNA; D013941:Thymine