Effects of CYP3A5 and MDR1 single nucleotide polymorphisms on drug interactions between tacrolimus and fluconazole in renal allograft recipients.
OBJECTIVE
Drug interactions between tacrolimus and azole antifungals are characterized by a large clinical variability. The aim of this study was to examine the influence of the CYP3A4, CYP3A5, and MDR1 single nucleotide polymorphisms on changes in tacrolimus exposure and dosing in renal allograft recipients treated with fluconazole.


METHODS
Twenty-nine patients who had received documented fluconazole treatment were identified out of a total of 753 renal recipients on maintenance tacrolimus therapy. These 29 patients were genotyped for CYP3A4*1/*1B, CYP3A5*1/*3, MDR1 C3435T, and G2677T/A, and the influence of the latter polymorphisms on tacrolimus exposure and dose before, during, and after fluconazole administration was examined.


RESULTS
Dose-corrected trough blood tacrolimus concentration did not change significantly from baseline (1.26+/-1.23-fold) in heterozygous CYP3A5*1 carriers during exposure to fluconazole, in contrast to homozygous CYP3A5*3 carriers (3.28+/-2.34-fold; P=0.04 between CYP3A5*3/*3 and CYP3A5*3/*1 genotypes). Homozygous CYP3A5*3 carriers experienced a significant decrease of weight-corrected tacrolimus dose requirements during fluconazole administration (54.7+/-23.7% from baseline, P<0.05) in contrast to heterozygous carriers of CYP3A5*1 (25.1+/-29.9%; P=0.07 between CYP3A5*3/*3 and CYP3A5*3/*1 genotypes). These findings were not influenced by fluconazole dose or duration of administration. Significantly more CYP3A5*3/*3 carriers were exposed to tacrolimus dose-uncorrected trough blood tacrolimus concentration value greater than or equal to 15 ng/ml during administration of fluconazole compared with CYP3A5*3/*1 carriers (73.9 vs. 16.7%, P=0.01).


CONCLUSIONS
In renal allograft recipients the CYP3A5*3/*1 genotype is associated with a reduced susceptibility for the inhibitory effects of fluconazole on tacrolimus metabolism, thereby identifying a genetic determinant of the clinical variability of CYP3A-mediated drug interactions.
Kuypers
Dirk R
DR
Department of Nephrology and Renal Transplantation, University Hospitals Leuven, University of Leuven, Leuven, Belgium. Dirk.Kuypers@uz.kuleuven.ac.be
de Jonge
Hylke
H
Naesens
Maarten
M
Vanrenterghem
Yves
Y
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage*; D005838:Genotype; D006801:Humans; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015725:Fluconazole; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus