The influence of diabetic status on the pharmacokinetics of clopidogrel and its metabolites in patients suffered from cardiovascular diseases

Marta Karaźniewicz-Łada; Dorota Danielak; Paweł Burchardt; Franciszek Główka

doi:10.20883/medical.e70

Authors

Marta Karaźniewicz-Łada Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poland
Dorota Danielak Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poland
Paweł Burchardt Division of Cardiology-Intensive Therapy, Department of Internal Medicine Poznan University of Medical Sciences, Poland
Franciszek Główka Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poland

DOI:

https://doi.org/10.20883/medical.e70

Keywords:

clopidogrel active metabolite, diabetes mellitus, platelet aggregation

Abstract

Aim. A significant percentage of individuals treated with an anti-platelet agent clopidogrel do not receive the expected therapeutic effect. Clopidogrel resistance is even more prevalent in patients with type 2 diabetes mellitus (DM). An extensive investigation on pharmacokinetics of clopidogrel and its metabolites in patients with type 2 DM suffering from cardiovascular diseases were performed following an administration of 75 mg of the drug.
Material and methods. Plasma concentrations of clopidogrel, its carboxylic metabolite (CLPM) and diastereoisomers of a thiol metabolite (the inactive H3 and the active H4) were determined by a validated HPLC-MS/MS method. The pharmacokinetic parameters of the analytes in diabetic (n = 16) and non-diabetic (n = 28) patients were compared and correlated with platelet aggregation.
Results. DM patients exhibited a slightly higher Cmax of clopidogrel (2.34 ± 2.29 ng/mL) compared with non-diabetic group (1.82 ± 1.86 ng/mL), whereas plasma levels of clopidogrel metabolites were lower in DM than in non-DM patients (2339 ± 989 ng/mL vs. 2662 ± 2090 ng/mL, 4.64 ± 4.79 ng/mL vs. 5.42 ± 4.55 ng/mL and 6.42 ± 4.80 ng/mL vs. 7.44 ± 7.18 ng/mL, respectively for CLPM, H3 and H4). A significant correlation was found between platelet aggregation and the Cmax of the active H4 metabolite in non-diabetic patients.
Conclusions. Pharmacokinetic parameters of clopidogrel, CLPM, H3 and H4 isomers in patients with DM did not differ significantly from those determined in non-diabetic group. Moreover, the antiplatelet response to clopidogrel therapy measured by ADP-stimulated platelet aggregation was similar in both groups of patients.

Downloads

Download data is not yet available.

References

Pereillo JM, Maftouh M, Andrieu A, Uzabiaga MF, Fedeli O, Savi P et al. Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Dispos. 2002 Nov;30(11):1288–95.

Jarvis B, Simpson K. Clopidogrel: a review of its use in the prevention of atherothrombosis. Drugs. 2000 Aug;60(2):347–77.

De Miguel A, Ibanez B, Badimon JJ. Clinical implications of clopidogrel resistance. Thromb Haemost. 2008 Aug;100(2):196–203.

Karaźniewicz-Łada M, Danielak D, Główka F. Genetic and non-genetic factors affecting the response to clopidogrel therapy. Expert Opin Pharmacother. 2012 Apr;13(5):663–83.

Farhan S, Höchtl T, Kautzky-Willer A, Wojta J, Huber K. Antithrombotic therapy in patients with coronary artery disease and with type 2 diabetes mellitus. Wien Med Wochenschr. 2010 Jan;160(1–2):30–8.

Angiolillo DJ, Suryadevara S. Aspirin and clopidogrel: efficacy and resistance in diabetes mellitus. Best Pract Res Clin Endocrinol Metab. 2009 Jun;23(3):375–88.

Ferreiro JL, Gómez-Hospital JA, Angiolillo DJ. Platelet abnormalities in diabetes mellitus. Diab Vasc Dis Res. 2010;7(4):251–259.

Erlinge D, Varenhorst C, Braun OÖ, James S, Winters KJ, Jakubowski JA et al. Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo. J Am Coll Cardiol. 2008 Dec 9;52(24):1968–77.

Farid NA, Kurihara A, Wrighton SA. Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans. J Clin Pharmacol. 2010 Feb;50(2):126–42.

Mani H, Toennes SW, Linnemann B, Urbanek DA, Schwonberg J, Kauert GF, Lindhoff-Last E. Determination of clopidogrel main metabolite in plasma: a useful tool for monitoring therapy? Ther Drug Monit. 2008 Feb;30(1):84–9.

Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010 Jan;38(1):92–9.

Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost. 2000 Nov;84(5):891–6.

Tuffal G, Roy S, Lavisse M, Brasseur D, Schofield J, Delesque Touchard N et al. An improved method for specific and quantitative determination of the clopidogrel active metabolite isomers in human plasma. Thromb Haemost. 2011 Apr;105(4):696–705.

Takahashi M, Pang H, Kawabata K, Farid NA, Kurihara A. Quantitative determination of clopidogrel active metabolite in human plasma by LCMSMS. J Pharm Biomed Anal. 2008 Dec 1;48(4):1219–24.

Karaźniewicz-Łada M, Danielak D, Teżyk A, Żaba C, Tuffal G, Główka F. HLCMSMS method for the simultaneous determination of clopidogrel, its carboxylic acid metabolite and derivatized isomers of thiol metabolite in clinical samples. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Dec 12;911:105–12.

Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol. 2010 Sep 14;56(12):919–33.

Di Girolamo G, Czerniuk P, Bertuola R, Keller GA. Bioequivalence of two tablet formulations of clopidogrel in healthy Argentinian volunteers: a single-dose, randomized-sequence, open-label crossover study. Clin Ther. 2010 Jan;32(1):161–70.

El Ahmady O, Ibrahim M, Hussein AM, Bustami RT. Bioequivalence of two oral formulations of clopidogrel tablets in healthy male volunteers. Int J Clin Pharmacol Ther. 2009 Dec;47(12):780–4.

Park KJ, Chung HS, Kim SR, Kim HJ, Han JY, Lee SY. Clinical, pharmacokinetic, and pharmacogenetic determinants of clopidogrel resistance in Korean patients with acute coronary syndrome. Korean J Lab Med. 2011 Apr;31(2):91–4.

Hall HM, Banerjee S, MGuire DK. Variability of clopidogrel response in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2011 Oct;8(4):245–53.

Gresner P, Dolnik M, Waczulikova I, Bryszewska M, Sikurova L, Watala C. Increased blood plasma hydrolysis of acetylsalicylic acid in type 2 diabetic patients: a role of plasma esterases. Biochim Biophys Acta. 2006 Feb;1760(2):207–15.

Harmsze AM, Van Werkum JW, Moral F, Ten Berg JN, Hackeng CM, Klungel OH et al. Sulfonylureas and on-clopidogrel platelet reactivity in type 2 diabetes mellitus patients. Platelets. 2011;22(2):98–102.

Geisler T, Anders N, Paterok M, Langer H, Stellos K, Lindemann S et al. Platelet response to clopidogrel is attenuated in diabetic patients undergoing coronary stent implantation. Diabetes Care. 2007 Feb;30(2):372–4.

Ang L, Palakodeti V, Khalid A, Tsimikas S, Idrees Z, Tran P et al. Elevated plasma fibrinogen and diabetes mellitus are associated with lower inhibition of platelet reactivity with clopidogrel. J Am Coll Cardiol. 2008 Sep 23;52(13):1052–9.

Bonello L, Armero S, Ait Mokhtar O, Mancini J, Aldebert P, Saut N et al. Clopidogrel loading dose adjustment according to platelet reactivity monitoring in patients carrying the 2C19*2 loss of function polymorphism. J Am Coll Cardiol. 2010 Nov 9;56(20):1630–6.