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Short Communication
"Influence of methadone on clopidogrel in addicts on
methadone maintenance therapy" Drug interaction
between methadone and clopidogrel
Ferigol Fallah 1
Abolhasan Hamidikenari (MD) 1
Seyed Navid Sajadi (Pharm.D) 2
Seyed Rohollah Sajadi (Pharm.D) 2
Background: Clopidogrel is a prodrug that converts in the liver to an active thiol
Mohammadreza Shiran (PhD) 3*

metabolite, which irreversibly inhibits the platelet P2Y12 adenosine diphosphate receptor. It seems that methadone as CYP2C19 inhibitor affects ticlopidine activity in vivo. This study aimed to test the ability of methadone in changing ticlopidine pharmacokinetics. Methods: We conducted a case–control study in 10 subjects. The cases (5 subjects) in our
study were addicts who were receiving methadone maintenance treatment (MMT) for preventing opium withdrawal symptoms. The control group were opiate users before 1. Psychiatry and Behavioral starting MMT. In both groups, the patients received clopidogrel (75mg/day) for 5 days. On Sciences Research Center, the 6th day, the subjects returned to the clinic, blood samples were taken up to 12 hours Mazandaran University of Medical Sciences, Sari, Iran. following clopidogrel dosing in case and control groups. Plasma concentration of 2. Molecular and Cell Biology clopidogrel was measured by GC-MAS. Noncompartmental pharmacokinetic analysis was Research Center, Mazandaran performed using Microsoft Excel software to estimate PK parameters. University of Medical Sciences, Sari, Iran. Results: In this study, methadone decreased clopidogrel clearance by 25% and increased
3. Immunogenetics Research the AUC0-inf nearly 1.3 fold during the coadministration of clopidogrel as an antiplatelet Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Conclusion: A significant decrease in the clearance of clopidogrel during the
coadministration of methadone consistent with a decrease in clopidogrel conversion to its active metabolite and this may decrease its efficacy and may have life-threatening consequences for the patients undergoing clopidogerel maintenance therapy. Keywords: Clopidogrel, Methadone, Interaction

* Correspondence:
Fallah F, Hamidikenari A, Sajadi SN, et al. "Influence of methadone on clopidogrel in addicts on Dr Mohammad-Reza Shiran, maintenance methadone therapy" Drug interaction between methadone and clopidogrel. Caspian J Department of Pharmacology, Intern Med 2016; 7(2):133-135. School of Medicine, Mazandaran University of Medical Sciences, Caspian J Intern Med 2016; 7(2):133-135
Sari, PO BOX: 48471-91971, Iran. The antiplatelet drug clopidogrel is an important therapeutic agent that is used
concomittant with aspirin or alone in patients with cardiovascular disease particularly after surgery to prevent recurrent of arterial stenosid (1). Clopidogrel is a prodrug that must be converted into an active thiol-containing metabolite before it can express antiplatelet E-mail: [email protected]
Tel: 0098 11 33543087
function (2). Pharmacokinetic studies indicated that clopidogrel is converted into its active Fax: 0098 11 33543087
metabolite by hepatic CYPs in a two-step oxidation process and CYP2C19 substantially contributes to both oxidative steps that generate the active clopidogrel metabolite. Methadone is a synthetic analgesic that is distinguished by its long duration of action, a property that makes it ideal for the treatment of chronic pain and for opioid withdrawal (3). Received: 14 Oct 2014
Lu et al (4) have shown that methadone is a mechanism-based inhibitor of CYP19. The Revised: 24 July 2015
Accepted: 15 Sep 2015
aim of the present study was to evaluate the effect of methadone as a mechanism based inhibitor of CYPC19 on the disposition of clopidogrel in MMT patients. Caspian J Intern Med 2015; 7(2):133-135
134 Fallah F, et al.
Table 2. Mean pharmacokinetic parameter values for
A case–control study was conducted in 10 subjects with clopidogrel in case and control groups estimated from
CYP2C19 extensive metabolizer (EM) genotype. The cases non- compartmental analysis
(5 subjects) in our study were those undergoing methadone maintenance thereatment (MMT). The control group was the Ratio of means
Mean±SD
opiate users before starting MMT. All patients gave written parameters
consent before recruitment and the study was approved by CL/F (L/hr)
the Research Ethics Committee of Mazandaran University of Medical Sciences. In both groups, the patients received clopidogrel (75mg/day) for 5 days. On the 6th day, the t1/2 beta (hr)
subjects returned to the clinic and before taking their daily dose of methadone (case group), 5 ml blood samples were provided at different time points of 0.5, 0.7, 2, 4, 8, and 12 AUC 0-inf (ng/hr/L)
hours following taking clopidogrel. In the control group, a 5 ml blood sample was taken at baseline and at the following time points: 0.5, 0.7, 2, 4, 8, and 12 hours following clopidogrel. Cmax (ng/ml)
Plasma concentration of clopidogrel was treated according to the method of Lagorce et al. (5) with some modifications. Noncompartmental pharmacokinetic analysis was performed using Microsoft Excel software to estimate clopidogrel PK parameters. Statistical analysis was performed using SPSS for Windows (Version.12, SPSS Inc., Chicago, USA). In all cases, p<0.05 was taken as statistically significant. A summary of demographic characteristics of patients along with their drug history is shown in table 1. Pharmacokinetics parameters values for clopidogrel in case and control groups are listed in table 2. Both, clopidogrel plasma concentrations (Cmax) and area under the concentration–time approximately 1.3 fold in MMT patients compared to control Figure 1: Mean plasma concentration–time profiles of
group. Although, there was a significant decrease in CL/F clopidogrel at steady state in case (bold line) and in
values in case group (P=0.03), however, there was no control treatment groups.
significant increase in t1/2 beta values (P=0.75). The mean concentration-time profile of clopidogrel after administration Discussion
of clopidogrel 75 mg for five days is shown in fig 1. To our knowledge, this is the first study which determined the effect of methadone on the disappearance of Table 1. Characteristics of subjects who completed the study
pharmacokinetics of the clopidogrel in patients on maintenance MMT therapy. Antiplatelet therapy with parameters
clopidogrel is a standard-of-care for the prevention and treatment of atherothrombotic cardiovascular disease and potential for drug–drug interactions, due to CYP2C19 Methadone dose (mg/day) Case inhibition, is an important clinical challenge in these groups of patients and often requiring careful monitoring. Many Caspian J Intern Med 2016; 7(2):133-135
Clopidogred interaction 135
4. Lu WJ, Bies R, Kamden LK, Desta Z, Flockhart DA. Methadone: a substrate and mechanism-based inhibitor pharmacodynamic response to clopidogrel. Methadone as an of CYP19 (aromatase). Drug Metab Dispos 2010; 38: accepted drug for the treatment of chronic pain and for opioid withdrawal in word (3) is a mechanism-based 5. Lagorce P, Perez Y, Ortiz J, Necciari J, Bressolle F. inhibitor of CYP19 (4). In this study, we demonstrated that Assay method for the carboxylic acid metabolite of concurrent administrations of methadone influence on clopidogrel in human plasma by gas chromatography- pharmacokinetics parameters of clopidogrel. The observed mass spectrometry. J Chromatogr B Biomed Sci Appl increases in the AUC of the clopidogrel with concomitant 1998; 720: 107-17. methadone appear to be due to inhibition of CYP2C19 6. Shuldiner AR. CYP2C19 and clopidogrel response: more enzyme or differences in p-gp or other CYPs activity than validation in the real world. Clin Pharmacol Ther between two groups. 2012; 91: 170-1. However our sample size in this study was too small and 7. Shuldiner AR, O'Connell JR, Bliden KP, et al. it needs to be confirmed in another case- control study by Association of cytochrome P450 2C19 genotype with the larger sample size by elucidating clopidogrel active antiplatelet effect and clinical efficacy of clopidogrel metabolite pharmacokinetics and its pharmacodynamics. therapy. JAMA 2009; 302: 849-57. 8. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354-62. We would like to thank the Research Council of 9. Giusti B, Gori AM, Marcucci R, Abbate R. Current status Mazandaran University of Medical Sciences for the financial of clopidogrel pharmacogenomics. Pharmacogenomics support, to Miss Bahar Ebrahimmagham from the Central 2012; 13: 1671-4. Research Laboratory of Mazandaran University of Medical 10. Simon T, Bhatt DL, Bergougnan L, et al. Genetic Sciences for GC-Mass analysis. polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and Funding: This manuscript is part of Ferigol Fallah's thesis.
antiplatelet response in healthy subjects. Clin Pharmacol This study has been supported by a grant from the Research Ther 2011; 90: 287-95. Council of Mazandaran University of Medical Sciences. 11. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic Conflict of Interest: None declared.
cardiovascular events. N Engl J Med 2009; 360: 363-75. 12. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 References
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Source: http://www.caspjim.com/article-1-418-fa.pdf