No pharmacokinetic interactions between mycophenolic acid and tacrolimus in renal transplant recipients

• Published in: Journal of clinical pharmacy and therapeutics Vol. 33; no. 2; pp. 193 - 201
• Main Authors: Kagaya, H., Miura, M., Satoh, S., Inoue, K., Saito, M., Inoue, T., Habuchi, T., Suzuki, T.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2008; Blackwell
• Subjects: Adult; Area Under Curve; Asian Continental Ancestry Group - genetics; Biological and medical sciences; CYP3A5; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - genetics; Drug Interactions; Female; Genotype; Glucuronosyltransferase - genetics; Humans; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - therapeutic use; interaction; Kidney Transplantation; Male; Medical sciences; mycophenolic acid; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - blood; Mycophenolic Acid - pharmacokinetics; Mycophenolic Acid - therapeutic use; Pharmacology. Drug treatments; Polymorphism, Genetic; Prodrugs - pharmacokinetics; Prodrugs - therapeutic use; tacrolimus; Tacrolimus - blood; Tacrolimus - pharmacokinetics; Tacrolimus - therapeutic use; UGT2B7; Mycophenolic acid; Isozyme; Glycosyltransferases; Transplantation; CYP3A5; Kidney; Surgery; Graft; Protein synthesis inhibitor; UDP-glucuronosyltransferase; Enzyme; Transferases; Cytochrome P450; Interaction; Lactone; Recipient; Macrolide; Immunomodulator; Treatment; Urinary system; Tacrolimus; Hexosyltransferases; Immunosuppressive agent; Pharmacokinetics; UGT2B7
• ISSN: 0269-4727; 1365-2710
• DOI: 10.1111/j.1365-2710.2008.00906.x

Summary 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 (AUC0–12) of MPA <70 μg·h/mL than in those with higher values AUC0–12 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 AUC0–12, 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 C0 groups: 5 ≤ C0 < 10, 10 ≤ C0 < 15 and 15 ≤C0 < 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. Conclusion:  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.