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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2009  |  Volume : 20  |  Issue : 6  |  Page : 991-994
Mycophenolate sodium increases cyclosporine blood levels in renal transplant recipients


1 Dr. Taheri Medical Research Group; Baqiyatallah University of Medical Sciences, Tehran, Iran
2 Dr. Taheri Medical Research Group, Tehran, Iran

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Date of Web Publication27-Oct-2009
 

   Abstract 

Cyclosporine is an immunosuppressive agent that displays a broad intra- and inter­individual pharmacokinetic variability. To evaluate the factors, which significantly influence cyclos­porine blood levels in our renal transplant recipients, we studied 611 consecutive patients trans­planted from living donors in Baqiyatallah hospital, Tehran, Iran from 1984 to 2005. The patients were divided into two groups: Group I included patients treated with mycophenolate sodium (MS) as an adjunctive immunosuppressive agent and Group II treated with azathioprine (AZA) as an adjunctive agent. Measurements of cyclosporine blood tough levels (C0) were performed 12 hours after the morning dose (just before the night dose). The mean age of the study population at time of transplantation was 38.7 ± 13.7 years and males formed 67% of it. Univariate analysis and multi­variable linear regression model showed that older age at transplantation, treatment with MS, and time interval from time of transplantation were significantly related with higher C0 levels. We conclude that there is an interaction of immunosuppressive agents in renal transplant patients with higher cyclosporine levels in the recipients of MS.

How to cite this article:
Pourfarziani V, Taheri S. Mycophenolate sodium increases cyclosporine blood levels in renal transplant recipients. Saudi J Kidney Dis Transpl 2009;20:991-4

How to cite this URL:
Pourfarziani V, Taheri S. Mycophenolate sodium increases cyclosporine blood levels in renal transplant recipients. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2019 Dec 7];20:991-4. Available from: http://www.sjkdt.org/text.asp?2009/20/6/991/57251

   Introduction Top


Cyclosporine (CsA), the core of immunosup­pressive agents used in kidney transplant pa­tients, has a narrow therapeutic window defined as a less than two fold difference in minimum toxic and minimum effective concentrations in blood. [1] Furthermore, this drug displays a broad intra and inter-individual pharmacokinetic va­riability. Therefore, monitoring of CsA levels is essential for its administration. [2] Definite target ranges have been proposed by different studies [3] to minimize the risk of allograft failure and ne­phrotoxicity associated with overdosing of CsA in organ transplant recipients.

Several factors are responsible for the wide variability in the blood bioavailability of CsA such as genetic factors (e.g. C3435T MDR1 po­lymorphism), [4] food (e.g. grape fruit juice), [5] and some other drugs (e.g. diltiazem). [6]

We aim in this study to evaluate the factors that may influence CsA blood levels in renal transplant recipients including the adjunctive im­munosuppressive agents (mycophenolate sodium (MS) and azathioprine, AZA).


   Methods Top


We studied 611 living renal allograft recipients transplanted in Baqiyatallah hospital, Tehran, Iran from 1984 to 2005. Patients were selected consecutively if they had complete demogra­phic data and at least one cyclosporine blood trough level (C0) test result. Patients were trea­ted by steroids (prednisolone), metabolic inhi­bitors (AZA and MS), and a calcineurin inhi­bitor (CsA, Neoral; ).

Patients were then divided into two groups, according to the type of their adjunctive immu­nosuppressive agents: Group I: consisted of pa­tients treated with MS and Group II: consisted of patients treated with AZA based therapy.

The CsA through concentrations were mea­sured by the EMIT; assay (Dade Behring Diag­nostics). CsA was administered in two divided dosages in all the patients including "morning dose" and "evening dose". Measurements were done 12 hours after the morning dose (just be­fore the night dose).


   Statistical Analysis Top


We used SPSS version 13.0 for Microsoft win­dows for data analysis. Quantitative variables are expressed as mean ± SD and independent sample t-test was used for analyzing them. Chi­ square test and Fisher's exact test were used for analyzing categorical variables.

Multivariate linear regression models were used for analyzing independent associations with cyclosporine concentrations. P value < 0.05 was considered significant.


   Results Top


Four hundred and eight (67%) of the study population and five hundred twelve (86%) do­nors were males. Mean age at the time of trans­plantation was 38.7 ± 13.7 years for the reci­pients and 27.7 ± 4.5 years for the donors. All grafts were obtained from living donors, and 96% was from unrelated donors. The cause of end-stage renal disease was hypertension in 114 (19%), diabetes mellitus in 86 (14%), glomeru­lonephritis in 81 (13%), polycystic kidney di­sease in 60 (10%), urologic disorders in 29 (5%), congenital disorders in 10 (2%), and other causes in 23 (4%). No cause for renal failure was men­tioned in 208 (34%) of patients.

One hundred and twenty (19.6%) patients re­ceived AZA based triple immunosuppressive the­rapy (group I), whereas 491 (80.4%) patients re­ceived MS (group II). [Table 1] shows compa­rable basic characteristics of both study groups. Group I revealed significantly lower C0 values and higher post transplantation creatinine levels at time of discharge from hospital than group II.

We used univariate linear regression model to assess C0 levels and its associations [Table 2]. Only age of patients at transplantation, type of metabolic inhibitor, and time interval from trans­plantation were significantly related with C0 le­vels. Multivariable linear regression model in­cluding all significant variables from univariate analysis showed that older age and MS adjunc­tive therapy were significantly associated with higher C0 levels [Table 2].


   Discussion Top


Several factors have been suggested to be res­ponsible for the high variability observed in cyclosporine bioavailability as a critical dose drug. It has been noted that African American and non-white South American transplant reci­pients have a poor absorption profile for drugs than Caucasians. [7] In case of CsA, a very high variability has seen even within specific ethnic populations. [8] Previous studies suggested a ma­jor role for genetic factors for this high varia­bility. [9]

Food-drug and drug-drug interactions have also been widely investigated. Certain types of food­drug interactions have also been reported in­fluencing absorption profiles of cyclosporine. Grape-fruit juice is one of the most important examples for these interactions. [5] Impact of se­veral drug such as diltiazem, [6] ketoconazole, [10] berberine, [11] and cyclosphosphamide [12] on the pharmacokinetics of cyclosporine has been investigated; it is demonstrated that diltiazem can improve bioavailability of cyclosporine in organ recipients. [6] However, although MS and AZA are the most frequently used adjunctive drugs in the organ recipients, there is scarcity of literature on the potential associations between these drugs and cyclosporine profiling.

To avoid over or under-immunosuppression, there is a global consensus that dosage regi­mens should be adjusted according to the whole­blood concentration. [1] The currently most wide­ly used parameter for therapeutic drug moni­toring of calcineurin inhibitors is the C0. In this study, we found that compared to patients on AZA adjunctive therapy, those who received MS had higher C0; equivalent dosages of CsA were prescribed for all the patients whether on MS or AZA. The higher concentration of CsA blood values observed with MS can be related to en­hanced intestinal absorption, or more likely due to a diminished rate of metabolism of CsA as a result of interaction with MS. This interaction is of relevance, since this may result in overex­posure to CsA and increase its adverse effects such as diabetes mellitus, nephrotoxicity, hyper­tension, and hyperlipidemia. [13]

In summary, our findings alert us that any efforts concerning therapeutic monitoring of cyclosporine blood levels in organ transplant recipients should consider interactions with mycophenolate sodium.

 
   References Top

1.Oellerich M, Armstrong VW, Kahan B, et al. Lake Louise Consensus Conference on cyclos­porine monitoring in organ transplantation: Report of the consensus panel. Ther Drug Monit 1995;17:642-54.  Back to cited text no. 1  [PUBMED]    
2.Nemati E, Einollahi B, Taheri S, et al. Cyclos­porine trough (C0) and 2-hour postdose (C2) levels: which one is a predictor of graft loss? Transplant Proc 2007;39(4):1223-4.  Back to cited text no. 2      
3.Levy G, Thervet E, Lake J, Uchida K. Consensuson Neoral C(2): Expert Review in Transplantation (CONCERT) Group. Patient management by Neoral C(2) monitoring: an international con­sensus statement. Transplantation 2002;73:S12.  Back to cited text no. 3      
4.Von Ahsen N, Richter M, Grupp C, Ringe B, Oellerich M, Armstrong VW. No influence of the MDR-1 C3435T polymorphism or a CYP3­A4 promoter polymorphism (CYP 3A4-V allele) on dose adjusted cyclosporin A trough concen­trations or rejection incidence in stable renal transplant recipients. Clin Chem 2001;47:1048-52.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Ducharme MP, Warbasse LH, Edwards DJ. Dis­position of intravenous and oral cyclosporine after administration with grapefruit juice. Clin Pharmacol Ther 1995;57(5):485-91.  Back to cited text no. 5      
6.Chrysostomou A, Walker RG, Russ GR, d'Apice AJ, Kincaid-Smith P, Mathew TH. Diltiazem in renal allograft recipients receiving cyclosporine. Transplantation. 1993;55(2):300-4.  Back to cited text no. 6      
7.Venkataramanan R, Swaminathan A, Prasad T, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet 1995;29:404-30.  Back to cited text no. 7  [PUBMED]    
8.Yu SF, Wu LH, Zheng SS. Genetic factors for individual administration of immunosuppressants in organ transplantation. Hepatobiliary PancreatDis Int 2006;5(3):337-44.  Back to cited text no. 8      
9.Kalow W, Tang BK, Endrenyi L. Hypothesis: comparisons of inter and intra-individual varia­tions can substitute for twin studies in drug research. Pharmacogenetics 1998;8:283-9.  Back to cited text no. 9  [PUBMED]    
10.Dominguez J, Kompatzki A, Foradori A, Noram­buena R. Ketoconazole alters cyclosporine pharmacokinetic profile and may predispose to acute rejection. Transplant Proc 2003;35(7): 2522-3.  Back to cited text no. 10      
11.Wu X, Li Q, Xin H, Yu A, Zhong M. Effects of berberine on the blood concentration of cyclos­porine A in renal transplanted recipients: cli­nical and pharmacokinetic study. Eur J Clin Pharmacol 2005;61(8):567-72.  Back to cited text no. 11      
12.Nagamura F, Takahashi T, Takeuchi M, et al. Effect of cyclophosphamide on serum cyclos­porine levels at the conditioning of hemato­poietic stem cell transplantation. Bone Marrow Transplant 2003;32(11):1051-8.  Back to cited text no. 12      
13.Cohen D, Galbraith C. General health manage­ment and longterm care of the renal transplant recipient. Am J Kidney Dis 2001;38:S10-24.  Back to cited text no. 13  [PUBMED]    

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Correspondence Address:
Saeed Taheri
Dr. Taheri Medical Research Group, Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqiyatallah Hospital, Mullasadra Ave, P.O. Box 14155-6437, Postal Code 1435915371, Tehran
Iran
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PMID: 19861858

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    Tables

  [Table 1], [Table 2]

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    Abstract
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