MDR-1 C3435T polymorphism influences cyclosporine a dose requirement in liver-transplant recipients.
BACKGROUND
Cyclosporine A (CsA) is characterized by high interindividual variations in oral bioavailability and a narrow therapeutic index. CsA is a substrate for P-glycoprotein, a member of the ABC transporter family encoded by the multiple drug-resistant gene MDR1.


METHODS
Because MDR1 gene exon 26 C3435T polymorphism influences intestinal P-glycoprotein expression, we investigated whether this polymorphism was correlated with variation in CsA dose requirement and concentration/dose ratio in 44 liver-transplant recipients during 1 month after transplantation. CsA concentration was measured 2 hours after administration (C2), according to international recommendations.


RESULTS
The MDR-1 wild-type genotype (3435CC) was observed in 15 patients (34%), whereas 21 (48%) patients were heterozygous (3435CT), and 8 (18%) patients were homozygous for the mutation (3435TT). There was no significant difference between the three groups regarding corticosteroids treatment or renal function during this period. One to 3 days after liver transplantation, when every patient received a similar CsA weight-adjusted dose, the concentration/dose ratio was correlated with exon 26 single nucleotide polymorphism and was significantly higher in subjects homozygous for the mutation (P=0.012). This was confirmed 1 month after transplantation (P=0.049), when the dose was adjusted to maintain the C2 target level of 1,000 microg/L and we observed that TT patients required approximately 50% lower weight-adjusted CsA dose than wild-type patients (P=0,033).


CONCLUSIONS
These findings demonstrate that the MDR1 exon 26 C3435T polymorphism is a major determinant of CsA concentration/dose ratio in liver-transplant recipients and is predictive of the dose of CsA to be administered to achieve the target C(2) concentration.
Bonhomme-Faivre
Laurence
L
Service Pharmacie-Pharmacologie, Hôpital Paul Brousse, Villejuif, France. laurence.bonhomme-faivre@pbr.ap-hop-paris.fr
Devocelle
Aurore
A
Saliba
Faouzi
F
Chatled
Skander
S
Maccario
Jean
J
Farinotti
Robert
R
Picard
Véronique
V
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D005938:Glucocorticoids / Q000008:administration & dosage; D006084:Graft Rejection / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000097:blood; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011239:Prednisolone / Q000008:administration & dosage
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011239:Prednisolone