The influence of genetic polymorphisms of cytochrome P450 3A5 and ABCB1 on starting dose- and weight-standardized tacrolimus trough concentrations after kidney transplantation in relation to renal function.
BACKGROUND
Cytochrome P450 3A5 (CYP3A5) and ABCB1 polymorphisms have been shown to influence tacrolimus (Tc) blood concentrations in the stable phase after organ transplantation. We hypothesized that Tc pharmacokinetics may be affected by genetic mutations subsequent to starting doses.


METHODS
We retrospectively analyzed data from a cohort of 59 kidney transplant recipients, in whom CYP3A5 (intron 3) and ABCB1 (exons 12, 21 and 26) genotypes were correlated to dose- and weight-standardized Tc trough concentrations obtained after initial Tc doses. Renal function, expressed as glomerular filtration rate (GFR) (MDRD equation), on days 7 and 14 after transplantation was evaluated and its relationship with Tc concentrations was analyzed.


RESULTS
Dose- and weight-standardized Tc trough concentrations were lower in patients carrying the CYP3A5 *1 allele (p<0.01). There was no statistically significant association with ABCB1 polymorphisms. In a multivariate analysis, both the presence of at least one CYP3A5 *1 allele (p=0.006) and age at the time of transplantation (p=0.010) were significant independent variables affecting Tc trough blood concentrations standardized to the first dosages (model r2=0.23). GFR was not affected by Tc concentrations.


CONCLUSIONS
Prospective trials are needed to prove that a genetic approach to Tc pharmacokinetics and its related side effects during the early period after grafting may improve patient outcome.
Mourad
Michel
M
Kidney and Pancreas Transplantation Unit, Université catholique de Louvain, Cliniques universitaires Saint Luc, Brussels, Belgium. michel.mourad@chir.ucl.ac.be
Wallemacq
Pierre
P
De Meyer
Martine
M
Brandt
Dimitri
D
Van Kerkhove
Valérie
V
Malaise
Jacques
J
Chaïb Eddour
Djamila
D
Lison
Dominique
D
Haufroid
Vincent
V
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D000368:Aged; D001835:Body Weight; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics; D007668:Kidney / Q000502:physiology*; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D027361:Organic Anion Transporters; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus