1199G>A and 2677G>T/A polymorphisms of ABCB1 independently affect tacrolimus concentration in hepatic tissue after liver transplantation.
OBJECTIVE
Tacrolimus is an immunosuppressive drug widely used in hepatic transplantation to avoid graft rejection. Its pharmacokinetics is characterized by a large interindividual variability requiring the use of therapeutic drug monitoring in daily clinical practice. Some genetic polymorphisms in biotransformation enzymes or transporter proteins, such as CYP3A5 and P-glycoprotein (ABCB1), in donors and/or recipients, appear as important determinants of the Tac blood pharmacokinetics. A recent study has shown that Tac hepatic tissue concentrations vary greatly among patients and are well correlated with graft outcome. The aim of our study was to investigate the effect of genetic polymorphisms in biotransformation enzymes (CYP3A5 and CYP3A7) or in their regulatory protein pregnane X receptor as well as in transporter proteins (ABCB1 and OATP-C) on Tac pharmacokinetics in liver transplant patients and more specifically on Tac hepatic concentrations.


METHODS
One hundred and fifty liver donors were genotyped for 13 different polymorphisms. Tac blood and hepatic concentrations were compared according to hepatic genotypes.


CONCLUSIONS
We confirmed that Tac dose requirement (on the basis of blood therapeutic drug monitoring) was higher among patients expressing hepatic CYP3A5 (at least one CYP3A5*1 allele) compared with patients who did not (CYP3A5*3/*3). Hepatic expression of CYP3A5, however, did not seem to influence Tac hepatic concentrations. In contrast, ABCB1 genetic polymorphisms significantly influenced Tac hepatic concentrations, whereas their impact on blood concentrations seemed negligible. Among these ABCB1 polymorphisms, the 1199G>A and 2677G>T/A single nucleotide polymorphisms seemed to reduce the activity of P-gp on Tac. As Tac hepatic concentrations have been significantly related to the graft outcome, it might be interesting, in the future, to genotype donors for ABCB1 polymorphisms to better individualize the Tac immunosuppressive therapy in hepatic transplantation.
Elens
Laure
L
Industrial Toxicology and Occupational Medicine Unit, Université catholique de Louvain, St Luc Hospital, Brussels, Belgium. laure.elens@uclouvain.be
Capron
Arnaud
A
Kerckhove
Valérie Van
VV
Lerut
Jan
J
Mourad
Michel
M
Lison
Dominique
D
Wallemacq
Pierre
P
Haufroid
Vincent
V
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004334:Drug Administration Schedule; D005787:Gene Frequency / Q000187:drug effects; D005838:Genotype; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D016014:Linear Models; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D016031:Liver Transplantation; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters / Q000235:genetics; D011110:Polymorphism, Genetic / Q000187:drug effects; D011687:Purines; D011743:Pyrimidines; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011687:Purines; D011743:Pyrimidines; C503999:SLCO1B1 protein, human; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C510164:CYP3A5 protein, human; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus