Elsevier

Electrochimica Acta

Volume 289, 1 November 2018, Pages 483-493
Electrochimica Acta

Voltammetric behaviour of the anticancer drug irinotecan and its metabolites in acetonitrile. Implications for electrochemical therapeutic drug monitoring

https://doi.org/10.1016/j.electacta.2018.09.094Get rights and content

Highlights

  • The voltammetric features of Irinotecan and its metabolites are rather complex.

  • The negative potential regions provides strongly overlapping processes at both GCE and Pt electrodes.

  • The oxidation process of the tertiary amine end of CPT-11 can be used for its detection.

Abstract

In this paper the voltammetric behaviour of the anticancer drug irinotecan (CPT-11), its injectable form in the clinical treatment regimen, irinotecan hydrochloride (CPT-11HCl), and its main metabolites (namely SN-38, SN-38G, APC, and NPC), and the natural chemical analogous camptothecin (CPT) were investigated in acetonitrile using a glassy carbon electrode (GCE), in view of developing an analytical protocol for the therapeutic drug monitoring (TDM) of CPT-11 in patients under chemotherapy regimens. Our results showed that all compounds provided rather complex cyclic voltammetric (CV) patterns in both the negative and positive potential regions.

The overall results indicated that the processes recorded in the negative potential region at both GCE and Pt electrodes could be hardly exploited for TDM applications, because of the overlapping of the peaks. Instead, in the positive potential region, the oxidation of the piperidine moiety of CPT-11, which was obtained in CPT-11HCl acetonitrile solutions basified with Na2B4O7 (synthetic solutions), proved to be useful for irinotecan quantification, as its process at the GCE took place over a potential region essentially free from interference. Preliminary differential pulse voltammetry (DPV) measurements performed in synthetic solutions of CPT-11HCl, over the concentration range 0.2–9 μM, showed a linear dependence between peak current and concentration with a satisfactory correlation coefficient of 0.992. The reproducibility was within 5% from three replicates.

Graphical abstract

Voltammogram recorded at a GCE in acetonitrile solution containing CPT-11HCl.

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Introduction

Irinotecan (7-ethyl-10[4-(piperidino)-1piperidino]-carbonyloxycamptothecin) (CPT-11) is a pro-drug currently used in several chemotherapy regimens [[1], [2], [3], [4], [5]]. It is activated by the enzyme liver-carboxylesterase (CE) to provide 7-ethyl-10-hydroxycamptothecin (SN-38) (Scheme 1) [5], which is a potent topoisomerase I inhibitor [[6], [7], [8]]. CPT-11 is also subject to extensive metabolic conversion by other enzyme systems providing several products such as 7-ethyl-10-[4-N-(5-aminopentanoicacid)-1-piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin (NPC). The latter, in turn, can be hydrolysed by CE to release SN-38 (Scheme 1) [7,8], which, by further enzymatic conversion, provides 7-Ethyl-10-hydroxy-camptothecin glucoronide (SN-38G) (Scheme 1) [7,8]. Because of this metabolic pathway, any analytical methodology, devised for the CPT-11 detection, has to face with possible interference due to the various metabolites, which share the skeleton structure of the plant alkaloid camptothecin (CPT) with CPT-11 (Scheme 2B) [9]. In addition, it must be considered that in clinical regimens, CPT-11 is administered as irinotecan hydrochloride (CPT-11HCl) [8] (Scheme 2A), whose analytical characteristics may be different from that of CPT-11 in its neutral amine form.

To date, most of analytical protocols developed for the detection of irinotecan are based on fluorescence [10,11] and hyphenated HPLC-MS and HPLC-fluorescence methods [[12], [13], [14], [15], [16], [17], [18]]. These approaches, though accurate, suffer from disadvantages related to costs, portability of the instruments, long time analysis, while measurements require centralized and well-equipped laboratories, and qualified personnel. Moreover, they are not very suited for controlling and personalizing drug dosages based on Therapeutic Drug Monitoring (TDM) [19], which is the clinical practice that allows administering the drug at the right dose and time, thus avoiding toxic effects, while maintaining efficacy [19].

Recently, electrochemical methods have gathered significant interest in TDM [[20], [21], [22], [23], [24], [25]], as they are prone for fast personalized point-of-care tests in therapeutic applications, particularly in oncology. In fact, cost effective, simplicity, portability and easy miniaturization of the instrumentation represent the main advantages of electroanalytical methods over those based on chromatography, mass spectrometry and spectroscopy [20]. Electrochemical-TDM approaches have been used for a variety of neurological drugs and neurotransmitters [21] and other therapeutic drugs [[22], [23], [24], [25]]. However, TDM in oncology is not a fully developed clinical practice yet, rather is very limited or even absent. Focusing on irinotecan, there are only a few reports dealing with its electrochemistry and/or quantification by electrochemical techniques [[26], [27], [28], [29], [30]]. Most of them refer to investigations performed in aqueous media [[26], [27], [28], [29]], and only a recent article has reported on the electrochemistry of CPT-11HCl (and CPT-11) in acetonitrile, and the aim was to establish the sites involved in the oxidation processes of the molecule [30]. As for the CPT-11 metabolites, to the best of our knowledge, no report exists on their electrochemical behaviour neither in aqueous nor in organic media. Broader information on the electrochemistry of CPT-11 and CPT-11HCl in organic solvents can be useful, in view of designing suitable electroanalytical protocols for their detection. In fact, organic solvents are already employed in clinical protocols to either denature proteins or extract the target analyte from biofluids [15,31]. On the other hand, knowledge on the electrochemical behaviour of the above-mentioned CPT-11 metabolites, which could strongly interfere in the CPT-11 detection, is also required. In addition, the redox behaviour of the different compounds can be useful to provide valuable insights in the activity or stability of the molecules in biological media, upon injection or removal of electrons from the molecules.

Considering the above scenario, in the present work, we examine comprehensively the voltammetric behaviour of: CPT-11 in its neutral and hydrochloride form, its main metabolites (SN-38, SN-38G, APC, NPC) and, for comparison, the natural chemical analogous of CPT-11, camptothecin (CPT, Scheme 2B) in acetonitrile solutions. The latter solvent has been chosen as it provided strong advantages with respect to aqueous solutions. Firstly, the wide electrochemical window of MeCN allowed a clear discrimination of the voltammetric pattern for all compounds involved in this study. Secondly, MeCN is also used as a solvent of election in common analytical methodologies, such as HPLC-MS, for the treatment of biofluids to extract and analyse drug molecules [15]. Cyclic voltammetric measurements are performed using glassy carbon and platinum electrodes. The latter is actually employed to investigate specifically the cathodic region and to ascertain the involvement in the electrode processes of acidic moieties present in the structure of the various compounds.

Section snippets

Chemicals

Acetonitrile (anhydrous, 99.9%), triethylamine, triethylammonium chloride (TrEAHCl), tetraethylammonium chloride (TEACl), tetrabutylammonium hexafluorophosphate (TBAPF6), tetrabutyl ammonium hydroxide (TBAOH), Tris(β-diketonato)ruthenium(III) (Ru(acac)3), irinotecan hydrochloride (CPT-11Cl), iso-quinoline and SN-38 were from Sigma Aldrich. SN-38G, APC, NPC and CPT were from Toronto research chemicals, Canada. Sodium tetraborate decahydrate (Na2B4O7·10H2O) was from Carlo Erba Reagents. Stock

Voltammetric behaviour of CPT-11HCl/CPT-11 and CPT

Fig. 1 shows typical cyclic voltammograms recorded at 200 mV s−1 at the GCE in 0.5 mM CPT-11HCl solutions. The CVs were generally run starting from 0 V vs. AgQR up to the solvent discharge, which occurred beyond about −2 and +2 V, respectively (Fig. 1A, black line). As it can be seen, a rather complex CV pattern is observed in both negative and positive potential regions, showing a series of peaks and redox processes, most of them with no associated peaks in the reverse scan. When the scan was

Conclusions and perspectives

In this work, the voltammetric behaviour of irinotecan and its main metabolites has been examined in detail in acetonitrile using a GCE as working electrode. The results showed that, because of their similar chemical structures, all compounds displayed voltammetric features strongly resembling one another, especially in the negative potential region. Measurements performed at a platinum electrode also displayed overlapping reduction processes, due to acidic moieties present in the various

Acknowledgements

The authors thank Associazione Italiana per la Ricerca sul Cancro (AIRC) for the financial support of this work (Project 12214: Innovative Tools for cancer risk assessment and early diagnosis −5 ×1000).

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