CYP3A and ABCB1 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of tacrolimus and its metabolites (M-I and M-III).
BACKGROUND
We prospectively studied renal transplant recipients receiving tacrolimus to determine the relationship between the CYP3A4, CYP3A5, and ABCB1 genetic polymorphisms and the pharmacokinetics (PK) and pharmacodynamics (PD) of tacrolimus and its metabolites.


METHODS
Renal transplant recipients receiving tacrolimus were genotyped for CYP3A4*4, CYP3A4*5, CYP3A4*18, CYP3A5*3, ABCB1 c.1236C→T, ABCB1 c.2677G→A/T, and ABCB1 c.3435C→T. Dose-adjusted trough concentration (C0) of tacrolimus and its metabolites (M-I and M-III) and PK and PD (T-cell and monocyte subsets) were determined on transplantation days -2, 5, 30, and 90 and correlated with the corresponding genotypes.


RESULTS
The dose-adjusted C0 of tacrolimus and its metabolites and AUC0-12 were significantly higher and the mean fluorescence intensity (MFI) of HLA/DR in monocytes was significantly lower in patients with CYP3A5*3/*3 than in patients with CYP3A5*1/*1 or CYP3A5*1/*3. However, there was no significant difference in the dose-adjusted C0 of tacrolimus and its metabolites, PK and PD among the ABCB1 genotypes. The MFI of HLA/DR in monocytes showed a significant negative correlation with dose-adjusted C0 of tacrolimus and its metabolites and AUC0-12. In a multiple regression analysis, the presence of the CYP3A5*3/*3 genotype was a significant independent variable determining the dose-adjusted C0 of tacrolimus and its metabolites, AUC0-12, and the MFI of HLA/DR in monocytes.


CONCLUSIONS
This study demonstrates that the CYP3A5 genetic polymorphisms are associated with the individual differences in PK and PD as well as in C0 of tacrolimus and its metabolites. The MFI of HLA/DR in monocytes might be considered to be a significant tool for monitoring tacrolimus efficacy.
Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, South Korea.
Se-Hee
SH
Yoon
Jang-Hee
JH
Cho
Owen
O
Kwon
Ji-Young
JY
Choi
Sun-Hee
SH
Park
Yong-Lim
YL
Kim
Young-Ran
YR
Yoon
Dong-Il
DI
Won
Chan-Duck
CD
Kim
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000379:methods; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects; D011110:Polymorphism, Genetic; D013601:T-Lymphocytes / Q000187:drug effects; D016559:Tacrolimus / Q000493:pharmacokinetics*; D016896:Treatment Outcome
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus