No influence of the MDR-1 C3435T polymorphism or a CYP3A4 promoter polymorphism (CYP3A4-V allele) on dose-adjusted cyclosporin A trough concentrations or rejection incidence in stable renal transplant recipients.
BACKGROUND
A substantial proportion of the variability in the absorption and clearance of cyclosporin A (CsA) after oral administration has been attributed to variability in liver cytochrome P-450 3A4 (CYP3A4) activity and intestinal P-glycoprotein (P-gp) concentration. A polymorphism in the CYP3A4 promoter region, termed "variant" allele CYP3A4-V, was postulated to be associated with altered CYP3A4 enzyme activity. A polymorphism in exon 26 (C3435T) of the multidrug resistance-1 (MDR-1) gene was correlated with intestinal expression and in vivo activity of P-gp.


METHODS
We investigated the occurrence of both polymorphisms in 124 stable Caucasian renal transplant recipients (>6 months after transplantation) on CsA as the primary immunosuppressant. Real-time, rapid-cycle PCR methods were developed and used for genotyping.


RESULTS
The estimated allele frequencies for the MDR-1 C3435T allele (54%) and the CYP3A4-V allele (4.8%) were similar to those reported for Caucasian populations. No significant differences were found for the CsA doses needed to maintain similar CsA trough concentrations in patients with and without the CYP3A4-V allele or in patients with different MDR-1 C3435T genotypes. Furthermore, neither of the polymorphisms investigated was associated with renal function as assessed by creatinine plasma concentration or, in a retrospective analysis, the incidence of acute rejection.


CONCLUSIONS
These findings suggest that the MDR-1 C3435T mutation and the CYP3A4-V variant are not major determinants of CsA efficacy in renal transplant recipients.
von Ahsen
N
N
Department of Clinical Chemistry, Georg-August-University, Robert-Koch-Strasse 40, 37075 Göttingen, Germany. nahsen@gwdg.de
Richter
M
M
Grupp
C
C
Ringe
B
B
Oellerich
M
M
Armstrong
V W
VW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000502:physiology; D016572:Cyclosporine / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000502:physiology; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000502:physiology; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D014180:Transplantation / Q000502:physiology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human