Effect of Ganciclovir on Pharmacokinetics of Mycophenolic Mofetil, in Kidney Transplant Patients

Document Type : Original Article

Authors

1 Department of Pharmacodinamy & Toxicology, School of Pharmacy & Pharmaceutical Research Center, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran

2 Nephrology Ward, Department of Internal Medicine, Imam-Reza Hospital, MUMS, Mashhad, Iran

3 Department of Medicinal Chemistry, School of Pharmacy & Pharmaceutical Research Center, MUMS, Mashhad,Iran

Abstract

Objective
Mycophenolate mofetil (MMF) is commonly administered concomitantly with ganciclovir for managing
transplant recipients who infected with CMV. This study was conducted to evaluate the probable effects of
ganciclovir on Mycophenolic acid (MPA) pharmacokinetic.
Materials and Methods
Ten kidney transplant recipients who full field inclusion and exclusion criterias enrolled in this study. The
first full profile blood sampling was taken during the combination therapy of gancyclovir and MMF. The
second sampling was taken one week after discontinuation of gancyclovir. Serum concentrations of MPA
and its glucuronide metabolite (MPAG) were determined by high-performance liquid chromatography
(HPLC) method. The pharmacokinetic parameters of MPA were measured, in two conditions, for each
patient.
Results
There was no significant difference between MPA clearance alone and in combination with ganciclovir
(28.221.9 L/h vs 31.921.3 L/h, p=0.207) and also no significant difference was seen between the MPA
Area Under the Curve (AUC) in two conditions (43.4816.27 μg/mlh vs 39.8020.18 μg/mlh, p=0.221).
MPAG AUC was increased significantly when the drugs were administrated in combination (957.8675.2
μg/mlh vs 134861095.1μg/mlh, p=0.036). Also ganciclovir induced entrohepatic recirculation of MPA in
two patients.
Conclusion
The pharmacokinetic parameter of MPA was not affected by ganciclovir. But ganciclovir increased MPAG
AUC and induced enterohepatic recirculation of MPA

Keywords


1. Allison AC, Eugui EM. Mycophenolate mofetile and its mechanism of action. Immunopharmacology 2000; 47:85-118.
2. Allison AC, Eugui EM. Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft regection. Transplantation 2005; 80(2S):181-186.
3. Mor E, Yussim A, Chodoff L, Schwartz ME. New immunosuppressive agents for maintenance therapy in organ transplantation. BioDrugs 1997 ;8(6):469-88.
4. Payen S, Zhang D, Maisin A, Popon M, Bensman A, Bouissou F, Loirat C, Gomeni R. Population pharmacokinetic of mycophenolic acid in kidney transplant pediatric and adolescent patients. Ther drug monit 2005; 27 (3):378-388.
5. Bullingham RE, Nichollos AJ, Kamm BR. Clinical pharmacokinetics of mycophenolate mofetil. Clin Pharmacokinet 1998; 34(6):429-55.
6. Johnson AG, Rigby RJ, Talor PJ, Jones CE, Allen J, Franzen K, Falk MC, Nicol D. The kinetics of mycophenolic acid and its glucuronide metabolite in adult kidney transplant recipients. Clin Pharmacol Ther 1999; 66(5):492-500.
7. Armstrong VW, Shipkova M, Schutz E, Weber L, Tonshoff B, Oellerich M. Monitoring of mycophenolic acid in pediatric renal transplant recipients. Transplantat Proc 2001; 33:1040–43.
8. Weber LT, Shipkova M, Armestrong VW. The pharmacokinetic-pharmacokinetic relationship for total and free mycophenolic acid in pediatric renal recipients; a report of german study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002; 13:759-768.
9. Matthew R, Weir. Medical Management kidney Transplants. Philadelphia 2005; 256-448.
10. Soulillo JP, Monnet JB. Mycophenolate mofetil dose not modify the incidence of cytomegalovirus (CMV) disease after kidney transplantation but prevents CMV-induced chronic graft dysfunction. J Am Soc Nephro 2001; 12:1758-63.
11. Buturovice-Ponikvar J, Kandus A, Malovrh M, Ponikvar R, Keveder R. Ganciclovir treatment for cytomegalovirus infections in renal transplant recipients. Transplant Proc 1992;24:1921-23.
12. Sommadossi JP, Bevan R, Ling T, Lee F,Master B, Chaplin MD,Nerenberg C, Kortez S, Buhles WS. Clinical pharmacokinetics of ganciclovir in patients with normal and impaired renal function. Rev Infec Dis 1988; 10 (suppl 3):S507-14.
13. Fleteher C, Sawchuk R, Chinnock B, de Miranda P, Balfour H. Human pharmacokinetics of the antiviral drug DHPG. Clin Pharmacol Ther 1986;40: 281-286.
14. Wolfe EJ, Mathur V, Tomlanovich S, Jung D, Wong R, Griffy K, Aweeka FT. Pharmacokinetics of mycophenolate mofetil and intravenous ganciclovir alone and in combination in renal transplantant recipients. J Pharmacotherapy 1997; 17(3):591-598.
15. Alto P. Roche global development, mycophenolate mofetil. Investigational brochure. 1994.
16. Shab J, Bullingham R, Rice P, Tsina L, Swaqn S, Halstenson C. Pharmacokinetics of oral mycophenolate mofetil and metabolits in renally impaired patients . Clin Pharmacol Ther 1995; 57:149.
17. Shaw LM, Koreck M, DeNofrio D, Brayman, KL. Pharmacokinetic pharmacodynamic and outcome investigations as the basis for mycophenolic acid therapeutic drug monitoring in renal and heart transplant patients. Clinical Biochemistry 2001; 34: 17–22.
18. Shipkova M, Armstrong VW, Kuypers D, Perner F, Fabrizi V, Holzer H, Wieland E, Ocllcrich M. Effect of cyclosporine withdrawal on mycophenolic acid pharmacokinetics in kidney transplant recipients with deteriorating renal function: preliminary report Ther Drug Monit 2001; 23:717-721.
19. Cattaneo D,Perico N,Gaspari F,Gotti E and Remuzzi G.Glucocoticoids interfere with mycophenolate mofetil in kidney transplantation.kidney International 2002;62:1060-1067.
20. Kobayashi M, Saitoh H, Kobayashi MI, Tadano K, Takahashi Y, Hirano T. Cyclosporin A, but not tacrolimus, inhibits the biliaty excretion of mycophenolic acid glucuronide possibly mediated by multidrug resistanceassociated protein 2 in rats. J.pharma Experim Therap 2004; 309(8): 1029-1035.