Influence of the CYP3A5 genotype on tacrolimus pharmacokinetics and pharmacodynamics in young kidney transplant recipients.
CYP3A enzyme plays a pivotal role in TAC metabolism. The aim of this study was to analyze retrospectively the influence of CYP3A5 gene polymorphism on TAC pharmacokinetics and pharmacodynamics in 30 teenage kidney transplant recipients. TAC dose, trough blood levels, apparent volume of distribution, as well as blood pressure and antihypertensive therapy obtained at different post-transplant periods, were correlated with the corresponding genotype. Despite a therapeutic monitoring strategy, heterozygotes (CYP3A5*1/*3) displayed a lower TAC blood concentration compared with homozygotes (CYP3A5*3/*3). Therefore, a two-fold increase of the daily TAC dose was required in the heterozygotes to reach the desired therapeutic target level. A significant group by time interaction effect was present for both variables (repeated measures ANOVA: p = 0.002) meaning a significant different pharmacokinetic response in these two cohorts. Mean blood pressure was also elevated in CYP3A5*1/*3 recipients despite similar antihypertensive treatment. This was parallel with an elevated apparent volume of distribution of TAC in this group. Thus, the allele-effect was correlated with one of the most common TAC side-effects suggesting a possible influence of CYP3A5 polymorphism on TAC pharmacodynamics. The authors concluded that a pre-emptive CYP3A5 pharmacogenetic screening could contribute to better individualization of TAC therapy.
Ferraresso
Mariano
M
Department of Surgical Sciences, University of Milan, Medical School, Milan, Italy. mariano.ferraresso@unimi.it
Tirelli
Amedea
A
Ghio
Luciana
L
Grillo
Paolo
P
Martina
Valentina
V
Torresani
Erminio
E
Edefonti
Alberto
A
D000293:Adolescent; D000328:Adult; D001794:Blood Pressure / Q000235:genetics; D002648:Child; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics*
D007166:Immunosuppressive Agents; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus