Effect of the ABCB1 3435C>T polymorphism on tacrolimus concentrations and dosage requirements in liver transplant recipients.
OBJECTIVE
The effect of ABCB1 3435C>T on tacrolimus concentrations in liver transplant recipients was studied. Tacrolimus is a substrate for P-glycoprotein, the product of the ABCB1 gene. To determine whether the ABCB1 single-nucleotide polymorphism (SNP) 3435C>T was associated with variation in the tacrolimus concentration:dose ratio (C:D) in 42 liver transplant recipients during three months after transplantation.


METHODS
Forty-two Caucasian patients who underwent an orthotopic liver transplantation from cadaveric donors received a basic immunosuppressive regimen containing tacrolimus and corticosteroids; mycophenolate mofetil was added in 18 cases. The SNP 3435C>T in exon 26 was investigated by MboI restriction-enzyme digestion, leading to the identification of CC, TT, or CT status at nucleotide 3435. Results obtained for the three genotypes were compared for each of three values: daily weight-adjusted tacrolimus dose, blood trough tacrolimus concentration, and C:D.


RESULTS
The wild-type genotype (3435CC) was observed in 10 patients (24%); 23 patients (55%) were heterozygous (3435CT) and 9 patients (21%) were homozygous for the mutation (3435TT). One to three days after liver transplantation, the mean +/- S.D. C:D was significantly higher in subjects homozygous for the mutation compared with subjects with the wild-type allele (236 +/- 119 ng . kg/mL . mg versus 104 +/- 74 ng . kg/mL . mg, respectively; p = 0.0167). Subjects with the heterozygous allele had an intermediate mean +/- S.D. C:D (131 +/- 108 ng . kg/mL . mg). One or three months after transplantation, no significant difference in the tacrolimus C:D was evident among the three groups.


CONCLUSIONS
The ABCB1 3435C>T polymorphism influenced the tacrolimus C:D in the first days after liver transplantation.
Bonhomme-Faivre
Laurence
L
Pharmacy-Pharmacology Service, Hôpital Paul Brousse, Villejuif, France. laurence.bonhomme-faivre@pbr.aphp.fr
Picard
Véronique
V
Saliba
Faouzi
F
Abbara
Chadi
C
Fodil
Madjid
M
Chaunoy
Mélanie
M
Farinotti
Robert
R
D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*
D007166:Immunosuppressive Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016559:Tacrolimus; C421109:multidrug resistance-associated protein 1