No pharmacokinetic interactions between mycophenolic acid and tacrolimus in renal transplant recipients.
OBJECTIVE
The aim of this study was to investigate drug interactions between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF) and tacrolimus, as well as the impact of CYP3A5 and UGT2B7 genetic polymorphisms on these drug interactions in 71 Japanese renal transplant recipients.


METHODS
Recipients received combination immunosuppressive therapy consisting of tacrolimus and MMF. On day 28 after transplantation, the concentrations of MPA and tacrolimus were measured by high-performance liquid chromatography and microparticle enzyme immunoassay respectively.


RESULTS
Acute rejection was over twice more common in recipients with a total area under the observed plasma concentration-time curve (AUC(0-12)) of MPA <70 microg x h/mL than in those with higher values AUC(0-12) values (17% vs. 7%). Using this cut-off AUC value, sensitivity was 70.6% and specificity 55.6% for acute rejection (AR). There was no change in AUC(0-12), maximum plasma concentration, trough plasma concentration, or oral clearance of tacrolimus with variation in dosage or AUC of MPA. There were also no significant differences in the MPA pharmacokinetic parameters among three tacrolimus C(0) groups: 5 < or = C(0) < 10, 10 < or = C(0) < 15 and 15 < or =C(0) < 20 ng/mL. Furthermore, there were no significant differences in MPA pharmacokinetic parameters between the UGT2B7*1/*1 and *1/*2 genotype groups having the CYP3A5*1 allele or the CYP3A5*3/*3 genotype.


CONCLUSIONS
Therapeutic dosages of MMF, do not significantly influence tacrolimus pharmacokinetics, and vice versa. Consequently, MPA and tacrolimus can be safely combined; however, it is necessary to monitor the plasma concentrations of each immunosuppressive agent to minimize acute rejection.
Kagaya
H
H
Department of Pharmacy, Akita University Hospital, Akita, Japan.
Miura
M
M
Satoh
S
S
Inoue
K
K
Saito
M
M
Inoue
T
T
Habuchi
T
T
Suzuki
T
T
D000328:Adult; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D011355:Prodrugs; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D009173:Mycophenolic Acid; D016559:Tacrolimus