Factors affecting the long-term response to tacrolimus in renal transplant patients: pharmacokinetic and pharmacogenetic approach.
BACKGROUND
The aim of our study was to determine the impact of CYP3A5*1 and CYP3A5*3 on the kinetics of tacrolimus in renal transplant recipients.


METHODS
Forty kidney recipients were selected to participate. Maintenance scheme consisted of tacrolimus, a purine inhibitor and a steroid. CYP3A5 genotyping was performed with PCR and RFLP. Pharmacokinetic model was developed with Linear Regression and General Linear Model repeated measures approach. The impact of sex, CYP3A5*1 allele, age at transplantation, hepatic and renal function on tacrolimus kinetics was examined.


RESULTS
The frequency of CYP3A5*3/*3 and CYP3A5*1/*3 genotype was 35/40 and 5/40, respectively. No CYP3A5*1/*1 was detected. CYP3A5*1 variant was associated with significant lower TAC dose adjusted concentration at 3, 6, 12 and 36 months after transplantation. Hepatic and renal function showed a significant effect on tacrolimus dose adjusted concentration 3 months after transplantation (p=0.000 and 0.028, respectively). Sex did not show a significant impact on tacrolimus kinetics. Carriers of CYP3A5*1 allele had lower predicted measures for tacrolimus dose adjusted concentration and higher predicted measures for volume of distribution.


CONCLUSIONS
We proved that CYP3A5*1 carriers need higher tacrolimus dose than CYP3A5*3 homozygotes to achieve the target blood concentration.
Katsakiori
Paraskevi F
PF
Department of Pharmacology, School of Medicine, University of Patras, Rion, Greece. vkatsak@med.upatras.gr
Papapetrou
Eirini P
EP
Sakellaropoulos
George C
GC
Goumenos
Dimitrios S
DS
Nikiforidis
George C
GC
Flordellis
Christodoulos S
CS
D000328:Adult; D000483:Alleles; D051544:Cytochrome P-450 CYP3A; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D013256:Steroids / Q000493:pharmacokinetics; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*
D013256:Steroids; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus