Quantitative determination of the antimalarials artemether and lumefantrine in biological samples: A review

Journal of Pharmaceutical and Biomedical Analysis 165 (2019) 304–314

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Review

Quantitative determination of the antimalarials artemether and lumefantrine in biological samples: A review Luisa Avelar Resende, Pedro Henrique Reis da Silva, Christian Fernandes ∗ Laboratório de Controle de Qualidade de Medicamentos e Cosméticos, Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Brazil

a r t i c l e

i n f o

Article history: Received 19 July 2018 Received in revised form 26 November 2018 Accepted 13 December 2018 Available online 13 December 2018 Keywords: Malaria Artemether Lumefantrine Biological matrices Sample preparation Liquid chromatography

a b s t r a c t Malaria is a worldwide health issue, with 216 million cases reported in 2016. Due to the widespread resistance of Plasmodium falciparum to conventional drugs, the first line treatment recommended by World Health Organization for uncomplicated malaria is artemisinin-based combined therapy (ACT), which combines two drugs with different mechanisms of action. The association of artemether and lumefantrine is the most common ACT used in the clinical practice. However, there have been reports of clinical artemisinin and derivatives partial resistance, which is defined as delayed parasite clearance. In this context, the monitoring of drug concentration in biological matrices is essential to evaluate treatment response, the need of dose adjustment and the occurrence of dose dependent adverse effects. Furthermore, it is also important for pharmacokinetic studies and in the development of generic and similar drugs. Determination of antimalarial drugs in biological matrices requires a sample pre-treatment, which involves drug extraction from the matrix and analyte concentration. The most used techniques are protein precipitation (PP), liquid-liquid extraction (LLE) and solid phase extraction (SPE). Subsequently, a liquid chromatography step is usually applied to separate interferences that could be extracted along with the analyte. Finally, the analytes are detected employing techniques that must be selective and sensitive, since the analyte might be present in trace levels. The most used approach for detection is tandem mass spectrometry (MS-MS), but ultraviolet (UV) is also employed in several studies. In this article, a review of the scientific peer-review literature dealing with validated quantitative analysis of artemether and/or lumefantrine in biological matrices, from 2000 to 2018, is presented. © 2018 Published by Elsevier B.V.

Contents 1. 2. 3. 4.

5.

6.

7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 Physicochemical and pharmacological properties of ATM and LUM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 Determination of artemether in biological samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 4.1. Sample preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 4.2. Separation and detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306 Determination of lumefantrine in biological samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 5.1. Sample preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 5.2. Separation and detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 Simultaneous determination of artemether and lumefantrine in biological samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 6.1. Sample preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 6.2. Separation and detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312

∗ Corresponding author. E-mail address: [email protected] (C. Fernandes). https://doi.org/10.1016/j.jpba.2018.12.021 0731-7085/© 2018 Published by Elsevier B.V.

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1. Introduction Malaria is an infectious disease caused by protozoan parasites of genus Plasmodium. Species associated to malaria in humans are P. falciparum, P. vivax, P. ovale and P. malariae [1]. The initial symptoms of malaria are nonspecific and similar to those of a viral infection. At this stage, it is considered uncomplicated, since there is no evidence of organ dysfunction. If not promptly and correctly treated, the disease can quickly progress to severe malaria, a life threatening condition [1]. At the beginning of 2016, malaria was considered to be endemic in 91 countries. In 2016, 216 million cases were estimated to have occurred globally, leading to 445,000 deaths. Most of the cases have occurred in Africa (90%) and Southeast Asia (7%). Approximately 80% of estimated cases in 2016 occurred in 15 countries. The majority of cases (99%) in Africa were due to P. falciparum malaria, while P. vivax was responsible for about 64% of cases in Americas [2]. The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) for the treatment of uncomplicated malaria caused by Plasmodium falciparum. The therapy consists of the combination of an artemisinin derivative and a longer acting antimalarial drug, which presents a different mechanism of action [1]. An estimated 409 million treatment courses of ACT were purchased by countries in 2016, an increase of about 30% when compared to 2015 [2]. The association of artemether (ATM) and lumefantrine (LUM) is the most common ACT used in endemic areas, and is available as an oral fixed-dose combination tablet (20 mg of ATM and 120 mg of LUM), developed by Novartis Pharmaceuticals and named Coartem. The use of ACTs is generally highly effective and well tolerated. However, in the recent years, resistance to artemisinins has arisen in P. Falciparum [1]. In this context, the monitoring of drug concentration in biological matrices is essential to evaluate treatment response, the need of dose adjustment and the occurrence of dose dependent adverse effects. Furthermore, the quantitative determination of antimalarials is also important for pharmacokinetic studies and in the development of generic and similar drugs. In 2013, Wahajuddin et al. published a review dealing with antimalarials determination by liquid chromatography [3]. Casas et al. also reviewed methods for determination of antimalarials, but they focused in sample preparation methods in different matrices [4]. In spite of being in-depth reviews on the subject, none of them has a focus on the association of ATM and LUM, the most commonly used anti-malarial treatment worldwide. In addition, after 4 years since the last review, several new methods have been developed. With all this in mind, the aim of this study is to summarize and critically evaluate the methods published in the peer-review literature for quantification of ATM and/or LUM in biological samples from 2000 to September 2018. A comprehensive review was performed highlighting the innovative approaches developed in the recent years.

Fig. 1. Chemical structures of the active metabolites dihydroartemisinin (DHA) and desbutyl-lumefantrine (DLM).

be included in this review the methods should be validated and indexed in the databases in the period from 2000 to September 2018. Manuscripts that employed methods that have been early published without any modification were excluded. After applying these inclusion/exclusion criteria, 40 articles were selected to be presented and discussed in this review. 3. Physicochemical and pharmacological properties of ATM and LUM The main physicochemical properties of artemether and lumefantrine are presented in Table 1. ATM, a semisynthetic artemisinin derivative, is a hydrophobic drug and does not have chromophores. It is active against the erythrocytic stages of the parasite, promoting inhibition of the synthesis of nucleic acids and proteins. ATM is rapidly metabolized by cytochrome P 450 (CYP450) into the active metabolite dihydroartemisinin (DHA) (Fig. 1). It has a rapid onset of action, but also a short elimination half-life (2–3 hours) [5–7]. Therefore, it is used to promote relief of the symptoms by reducing the number of circulating parasites [1]. LUM, an aryl amino alcohol, is a weak base, highly lipophilic and absorbs strongly in the UV region. It is slowly absorbed and metabolized by CYP450 into the active metabolite desbutyl-lumefantrine (DLM) (Fig. 1). It has a half-life of 2–3 days in healthy human volunteers and 4–6 days in patients infected with P. falciparum. Absorption of LUM is highly dependent on food intake, and usually starts after a lag-time of up 2 h, with maximum plasma concentrations after 6–8 hours. LUM is a blood schizonticide responsible for elimination of residual parasites [8]. 4. Determination of artemether in biological samples The methods published for ATM determination in biological samples are described in Table 2. 4.1. Sample preparation

2. Search strategy The search for articles dealing with quantification of ATM and/or LUM in biological samples was performed in Web of Knowledge and Scopus databases. The search terms used to find articles related to artemether determination were: “artemether” AND “chromatography” AND “plasma” OR “blood. 129 and 124 articles were retrieved from Web of Knowledge and Scopus, respectively. The search terms “lumefantrine” AND “chromatography” AND “plasma” OR “blood” were employed to find articles related to lumefantrine analysis; in this case, 75 and 63 articles were retrieved from Web of Knowledge and Scopus, respectively. In both cases, the terms were searched in Article title, Abstract and Keywords. To

Plasma has been the matrix investigated in all studies for ATM. Peys et al. additionally determined ATM and DHA in human urine [11]. Different pre-treatments and extraction techniques have been employed for determination of ATM in plasma. Liquid-liquid extraction was applied in 5 out of the 18 studies evaluated (12 studies related to the determination of ATM alone and 6 studies dealing with simultaneous determination of ATM and LUM), due to its simplicity and efficiency. Three of the authors used ethyl acetate as the organic solvent, in which ATM is freely soluble. The recovery rates ranged from 72.0 to 110.0%, and the sample volumes from 100 to 1000 ␮L. However, liquid-liquid extraction has gradually been replaced by techniques that require lower volumes of organic

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Table 1 Physicochemical properties of artemether and lumefantrine. pka

logP

White crystals or 86-88 a white, crystalline powder

No ionizable groups

2.8

A yellow crystalline powder

8.7 and 13.4

8.7

Compound

CAS number Structure

Molecular formula

Molar mass Solubility (g/mol)

Description

Artemether

71963-77-4

C16 H26 O5

298.37

Practically insoluble in water; very soluble in dichloromethane and acetone; freely soluble in ethyl acetate and dehydrated ethanol

C30 H32 Cl3 NO 528.94

Practically insoluble in water; soluble in dichloromethane; slightly soluble in methanol

Lumefantrine 82186-77-4

Melting point (o C)

128-132

Source: CAS, 2018 [9] and The International Pharmacopeia, 2017 [10].

solvent, in order to minimize the use and disposal of hazardous substances and the exposure of the analyst to toxic gases. Magalhães et al. employed two phase liquid-phase microextraction (LPME) prior to chromatographic analysis. LPME is a miniaturized version of liquid-liquid extraction based on the equilibrium between the analyte in the sample and in an acceptor phase, supported on a hollow fiber membrane (Fig. 2). The diameter and the pore size of the fiber employed by the authors were 600 and 0.2 ␮m, respectively, which culminated in reduced consumption of organic solvent (20 ␮L of toluene:n-octanol, injected into the lumen) compared to other methods. The recovery percentage was 32.5%, consistent with other studies reported employing LPME for different drugs, but considerably lower than those obtained in the studies employing conventional LLE [17]. Protein precipitation has been employed in 6 methods. Acetonitrile or methanol, alone or with acetic acid, were the precipitant agents mostly used. Samples were mixed, centrifuged, and the supernatant was evaporated and reconstituted in the mobile phase used in the chromatographic system. Sample volumes varied from 50 to 960 ␮L. The use of acetonitrile as the organic solvent resulted in higher recoveries, 86.0–100.5, whereas the use of methanol resulted in recoveries ranging from 51.5-88.7. This result was expected, since acetonitrile has protein precipitation efficiency higher than methanol [22]. Five authors used solid phase extraction (SPE). Poly(divinylbenzene-co-N-vinylpyrrolidone), commercially named Oasis HLB, was the sorbent used in these studies. Huang et al. analyzed plasma samples from patients infected with malaria parasites and observed degradation of ATM and DHA when precipitation of hemoglobin with organic solvent occurs. It has been postulated that Fe2+ in hemoglobin or its derived products from malaria patients caused degradation, and then the authors developed a method with H2 O2 as a stabilizing agent for ATM and DHA. In this study, the volume of plasma sample was only 50 ␮L and a micro-elution plate (containing 2 mg of sorbent per well), suitable for small sample volume, was employed [14]. Huang et al. have also employed SPE for sample preparation. A 500 ␮L aliquot of human plasma was loaded onto a SPE column, and eluted with acetonitrile:methyl acetate (90:10). The recoveries ranged from 72.8 to 80.9, a result considered relatively low, but consistent, reproducible and repeatable according to the authors [18].

Fig. 2. LPME apparatus used by Magalhães et al. [17]. Reprinted from Talanta, v. 81, Magalhães, I.R.S.; Jabor, V.A.P.; Faria, A.M.; Collins, C.H.; Jardim, I.C.S.F.; Bonato, P.S., Determination of ␤-artemether and its main metabolite dihydroartemisinin in plasma employing liquid-phase microextraction prior to liquid chromatographic–tandem mass spectrometric analysis, p. 941–947, 2010, with permission from Elsevier.

In general, the use of liquid-liquid extraction as sample pretreatment resulted in higher recoveries. However, due to the high consumption of organic solvent in LLE, SPE has proven to be a plausible option, with acceptable recovery rates reported.

Table 2 Methods for determination of ATM in biological samples. Metabolites

Sample volume (␮L)

Sample preparation

Solvent/ sorbent

IS

Chromatography

Detection

LOQ (ng/mL)

Recovery (%)

Reference

Human plasma

DHA

100

LLE

Ethyl acetate

Artemisinin

APCI-MS (m/z 267)

0.8

77-86

KHUDA et al., 2016 [7]

Mouse plasma

DHA

n.f.

SPE

Poly(divinylbenzeneco-N-vinylpyrrolidone)

Isotope labeled ATM.

MS/MS (m/z 283 → m/z 265)

n.f.

n.f.

MORADIN et al., 2016 [12]

Human plasma

DHA

50

SPE

Poly(divinylbenzeneco-N-vinylpyrrolidone)

Isotope labeled ATM

62.6-63.8

HILHORST et al., 2014 [13]

DHA

50

SPE

Poly(divinylbenzeneco-N-vinylpyrrolidone)

Isotope labeled ATM

APCI-MS/MS (m/z 253.2 → m/z 163.1) ESI-MS/MS (m/z 316 → m/z 267)

1.0

Human plasma

0.5

116.0-122.0

HUANG et al., 2013 [14]

Sheep plasma

DHA and DHAG

300

PPT

Methanol

Artesunate

ESI-MS/MS (m/z 267.4 → m/z 163.0)

93.8

51.5-76.2

DUTHALER et al., 2011 [15]

Human plasma

DHA

100

LLE

Ethyl acetate

Isotope labeled ATM

ESI-MS/MS (m/z 316.2 → m/z 163.1)

2.0

76.5-80.1

WIESNER et al., 2011 [16]

Human plasma

DHA

1000

LPME

Toluene:n-octanol (1:1)

Artemisinin

ESI-MS/MS (m/z 267 → m/z 163)

5.0

32.5

MAGALHÃES et al., 2010 [17]

Human plasma

DHA

500

SPE

Poly(divinylbenzeneco-N-vinylpyrrolidone)

Artemisinin

ESI-MS/MS (m/z 316 → m/z 267)

2.0

72.8-80.9

HUANG et al., 2009 [18]

Human plasma

DHA

50

SPE

Poly(divinylbenzeneco-N-vinylpyrrolidone)

Isotope labeled ATM

65.4- 77.9

HANPITHAKPONG et al., 2009 [19]

DHA

100

LLE

Methyl t-butyl ether

Artemisinin

5.0

91.5-99.4

SHI et al., 2006 [20]

Human plasma and urine

DHA

LLE

2,2,4-trimethyl pentane:ethyl acetate (7:3)

Artemisinin

10.0 (plasma) 5.0 (urine)

DHA

LLE

1-chlorobutane: isooctane (55:45)

Artemisinin

97.9 – 110.1 (plasma) 95.9 – 106.8 (urine) 72.0–77.0

PEYS et al., 2005 [11]

Human plasma

1000 (Plasma) 2000 (Urine) 500

ESI-MS/MS (m/z 316 → m/z 163) APCI-MS/MS (m/z 221.00 → m/z 163.00) ESI-MS (m/z 267.2)

1.43

Human plasma

C18 (150 x 4.6 mm, 5.0 ␮m) Acetonitrile: water with 0.1% formic acid (80:20) C18 Acetonitrile:water:formic acid (50:50:0.1) C18 (50 x 2.1 mm, 3.5 ␮m) Acetonitrile:0.1% ammonia – gradient elution C18 (100 x 2.1 mm, 1.8 ␮m) Acetonitrile with 0.1% formic acid:ammonium formate (10 mM, pH 4.0) – gradient elution C18 (20 x 2.1 mm, 3.0 ␮m) Acetonitrile with 0.15% formic acid: aqueous 5 mM ammonium formate with 0.15% formic acid - gradient elution Pentafluorophenyl (50 x 2.0 mm, 5.0 ␮m) Methanol: aqueous ammonium acetate (10 mM) with 0.1% acetic acid (65:35) Poly(methyltetradecylsiloxane) immobilized onto a doubly zirconized-silica support (150 x 3.9 mm, 5 ␮m) Methanol: aqueous ammonium acetate (10 mM, pH 5.0) (80:20) C18 (150 x 4.6 mm, 5.0 ␮m) Acetonitrile with 0.1% formic acid:aqueous ammonium formate (10 mM, pH 4.1) (80:20) C18 (100 × 2.1 mm, 5.0 ␮m) Methanol:ammonium acetate (10 mM, pH 3.5) (70:30) C18 (150 x 4.6 mm, 5.0 ␮m) Acetonitrile:0.1% formic acid (80:20) C18 (150 x 4.6 mm, 5.0 ␮m) Acetonitrile: aqueous ammonium acetate 10 mM with 0.1% glacial acetic acid C18 (150 x 4.6 mm, 5.0 ␮m) Acetonitrile:0.1% glacial acetic acid (66:34)

APCI-MS (m/z 267)

5.0

L.A. Resende et al. / Journal of Pharmaceutical and Biomedical Analysis 165 (2019) 304–314

Matrix

SOUPPART et al., 2002 [21]

APCI: atmospheric pressure chemical ionization; DHA: dihydroartemisinin; DHAG: dihydroartemisinin-glucuronide; ESI: electrospray; IS: Internal Standard; LOQ: limit of quantification; LLE: liquid-liquid extraction; LPME: liquid-phase microextraction; MS/MS: tandem mass spectrometry; n.a.: not analyzed; n.f.: not found; PFP: pentaflourophenyl; PPT: protein precipitation; SPE: solid phase extraction. 307

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4.2. Separation and detection

5. Determination of lumefantrine in biological samples

Reversed-phase liquid chromatography was the separation mode chosen in all methods, though the pentafluorophenyl (PFP) stationary phase used by Wiesner et al. [16] can exhibit ionexchange interactions depending on the conditions used. C18 (octadecylsilane) stationary phase have been employed in most studies. Magalhães et al. tested a laboratory-made column based on poly(methyltetradecylsiloxane) immobilized onto a doubly zirconized-silica support, due to its desirable chemical and thermal properties [17]. Both isocratic and gradient elution has been employed for the analysis of ATM and DHA, in order to obtain sharp and satisfactory peak shapes. Acetonitrile or methanol have been used as the organic modifier in the mobile phase. Furthermore, addition of ammonium compounds into the mobile phase was employed, since it is important for detection of the ammonium adduct [M + NH4]+ of ATM, when mass spectrometry was used. Detection has been performed mainly by tandem quadrupole mass spectrometry (MS-MS). Two ionization techniques have been described for ATM: atmospheric pressure chemical ionization (APCI) and electrospray ionization (ESI), both in positive ion mode. When APCI was used, the most employed precursor ion was that with m/z 267 (corresponding to MH+ −CH3 OH), while m/z 163 was the product ion most used. On the other hand, precursor ions with m/z 267 and 316 (corresponding to the ammonium adduct M + NH4 + ) and fragment with m/z 163 were the most utilized with ESI. Souppart et al. employed mass spectrometry in single ion monitoring mode using APCI, a harsher ionization method compared to ESI. Protonated molecules (MH+ ) of ATM and DHA were not found, and the method was fully validated using the ion with m/z 267 for ATM and DHA (MH+ −OH) [21]. More recently, Khuda et al. have chosen APCI due to its high sensitivity, and appropriate response. The authors obtained a concentration of 0.8 ng/mL as the limit of quantification (LOQ), one of the lowest values found [7]. Generally, ESI has been the most utilized technique, through monitoring of the ammonium adduct of ATM. The limits of quantification obtained in the methods ranged from 0.5 to 600 ng/mL. The ionization technique chosen in mass spectrometry has not resulted in significant difference in the limits of quantification. Huang et al. pointed out the importance of a low LOQ for the assay, since ATM and DHA have a short half-life in human patients, and blood concentration is rapidly dropped under 10 ng/mL [18]. Validation of the methods has been mostly conducted following the Guidance for Industry in BioAnalytical Method Validation, published by the Food and Drug Administration (FDA). All authors used addition of internal standards into the samples, to compensate matrix interferences. The most used internal standards used were artemisinin, artesunate and deuterated-artemether. All methods described in the literature for the determination of artemether employed plasma as the biological matrix. It can be said that solid phase extraction is an adequate sample preparation approach to be used with plasma samples. Despite having lower recoveries than those obtained with liquid-liquid extraction, it uses less solvent and has higher selectivity. In the separation stage, the use of reversed phase liquid chromatography is the ideal condition, since artemether is a non-polar drug (logP 2.8). Detection should be performed by mass spectrometry, since artemether does not have adequate chromophore that allows its determination by spectrophotometry in the ultraviolet region with appropriate detectability.

The methods published for determination of LUM are summarized in Table 3. 5.1. Sample preparation Plasma has been the most frequently investigated matrix. Besides the use of plasma samples, whole blood has also been investigated for LUM. Govender et al. argued that the choice of whole blood instead of plasma might be beneficial for clinical trials conducted in resource-limited areas [28]. Blessborn et al. collected samples using the dried blood spot (DBS) approach, which is less invasive than venipuncture, and more cost effective for storage and transportation. However, introduction of the paper matrix makes the extraction, with high recovery, of the drug from blood more difficult [37]. Protein precipitation has been the most used technique for sample preparation, since LUM is a lipophilic drug with high protein binding rate (> 99%) [44]. The recovery is increased because during PPT, the bonds between LUM and plasma proteins are disrupted and the drug is released to sample solution. Acetonitrile or methanol were added to volumes of samples ranging from 20 to 960 ␮L. The use of acetonitrile resulted in better recovery rates, when compared to methanol. Wahajuddin et al. tested several organic solvents, including acetic acid, trichloroacetic acid, methanol and acetonitrile. Acetonitrile was chosen because higher extraction efficiency for LUM and cleaner samples were obtained [27]. Due to the high protein binding rate of LUM, SPE has not been usually used alone for extraction, but following a PPT step. For SPE, most methods used C8 material as the sorbent. Blessborn et al. detected six antimalarial drugs in whole blood in a screening assay. They employed PPT followed by SPE, but satisfactory recovery values for LUM (20%) were not obtained. The authors explained the low recovery based on the absence of pretreatment of the sampling paper with tartaric acid, which has been previously reported to increase stability and recovery of LUM [37]. Recently, Silva et al. developed a molecularly imprinted solid phase extraction method for selective extraction of LUM from human plasma samples. The polymer obtained exhibited affinity approximately 50% higher for LUM compared to halofantrine, a drug with similar structure. Also, recoveries in the range of 84% were observed [23]. Ten authors employed liquid-liquid extraction, using mainly hexane and ethyl acetate, alone or in a mixture of these two organic solvents. The sample volumes varied from 10 to 500 ␮L. Huang et al. developed a method with small sample volume to support pediatric studies. Plasma samples of 25 ␮L were acidified with 5% formic acid prior to extraction with 900 ␮L of ethyl acetate, resulting in recoveries higher than 80%. The acidification of the sample was important for disruption of protein binding [31]. 5.2. Separation and detection Reversed phase chromatography has been usually used for separation of LUM. In the early studies, UV was the detector used. More recently, mass spectrometry has been generally employed for detection, because of its high sensitivity and selectivity. Several stationary phases have been employed in reversed phase chromatography, for instance C18, C16, C8, cyano and phenyl. The particle sizes of the columns mostly used were 3–5 ␮m. Silva et al. used a C18 column (20 x 2.1 mm, 1.9 ␮m) and achieved a total chromatographic run of only 2.2 min [26]. The use of a column with particles size smaller than 2.0 ␮m characterizes Ultra-high Performance Liquid Chromatography (UHPLC), a technique with enhanced resolution and speed. Recently, C18 column packed with core shell particles with 2.6 ␮m was employed in another

Table 3 Methods for determination of LUM in biological samples. Sample volume (␮L)

Sample preparation

Solvent/ sorbent

IS

Chromatography

Detection

LOQ (ng/mL)

Recovery (%)

Reference

Human plasma

n.a.

500

PPT and SPE

Halofantrine

Core-shell C18 (100 x 4.6 mm, 2.6 ␮m) Methanol:acetonitrile:TFA 0.14% (50:33:17)

UV (305 nm)

15.0

84.3

SILVA et al., 2018 [23]

Human whole blood

n.a.

25-50

LLE

Acetonitrile with 0.2% perchloric acid (PPT) and MIP (SPE) Water and acetone with 5% formic acid

Isotope labeled LUM

MS/MS (m/z 528 → m/z 510)

100.0

32.0-88.0

IPPOLITO et al., 2018 [24]

Human whole blood

DLM

10

LLE

MeOH with 1% formic acid

Isotope labeled LUM

ESI-MS/MS (m/z 531.1 → m/z 512.1)

20.0

58.3-124.6

GALLAY et al., 2018 [25]

Human plasma

DLM

100

PPT

Acetonitrile

Isotope labeled LUM

C8 (50 x 2.1 mm, 5.0 ␮m) Acetonitrile with 0.1% formic:ammonium formate 10 mM, pH 4.0 – Gradient elution C18 (75 x 2.1 mm, 3.5 ␮m) Acetonitrile + 0.1% formic acid and 2 mM ammonium acetate + 0.1% formic acid – Gradient elution C18 (20 x 2.1 mm, 1.9 ␮m) Methanol with formic acid 0.5%:formic acid 0.5% in water – Gradient elution

ESI-MS/MS (m/z 528.2 → m/z 510.2)

21.0

SILVA et al., 2015 [26]

Rat plasma

n.a

100

PPT

Acetonitrile

Halofantrine

ESI-MS/MS (m/z 529.0 → m/z 511.3)

3.9

Mouse whole blood and plasma

n.a.

20

PPT

0.1% formic acid and acetonitrile (1:3)

Isotope labeled LUM

C18 (50 x 4.6 mm, 5.0 ␮m) Acetonitrile:Methanol (50:50) and ammonium formiate buffer (10 mM, pH 4.5, 95:5) Pentafluorophenyl (50 x 2.0 mm, 5.0 ␮m) Acetonitrile:0.1% formic acid (30:70)

19.6 (citrate) 29.5-44.2 (heparin) 23.6-26.6 (EDTA) 94.6-109.6

ESI-MS/MS (m/z 530.1 → m/z 347.8)

15.6

GOVENDER et al., 2015 [28]

Human plasma

DLM

200

PPT and LLE

Meloxicam

C18 (150 x 4.6 mm, 5.0 ␮m) Acetonitrile:0.05% trifluoroacetic acid (70:30)

UV (335 nm)

18.0

Human plasma

n.a.

100

PPT

Acetonitrile (PPT) Hexane:ethyl acetate (75:25) (LLE) 0.5% acetic acid acetonitrile solution

83.6-106.5 (whole blood) 100.5-114.2 (plasma) 87.80–89.11

Halofantrine

UV (300 nm)

125.0

101.0-103.0

MAGANDA et al., 2013 [29]

Human plasma

n.a.

100

PPT

Acetonitrile

Halofantrine

UV (335 nm)

52.9

n.f.

MWEBAZA et al. (2013) [30]

Human plasma

n.a.

25

LLE

5.0% aqueous formic acid and ethyl acetate

Isotope labeled LUM

ESI-MS/MS (m/z 528 → m/z 510)

50.0

81.0–84.3

HUANG et al., 2012 [31]

Human plasma

n.a.

500

LLE

Halofantrine

UV (335 nm)

n.a.

n.a.

MINZI et al., 2012 [32]

Rat plasma

DLM

100

LLE

Diethyl ether: ethyl acetate (2:1) n-hexane

C16 (150 x 4.6 mm, 3.0 ␮m) 0.1% trifluoroacetic acid in acetonitrile: 0.01% trifluoroacetic acid in ammonium acetate (0.1 M) – gradient elution Phenyl (150 x 4.6 mm, 5.0 ␮m) Acetonitrile:ammonium acetate buffer (0.1 M, pH 6.5) (10:90) C8 (50 x 2.1 mm, 5.0 ␮m) Acetonitrile with formic acid 0.1%:aqueous ammonium formate (10 mM, pH 4.0) – gradient elution C18 (125 x 4.0 mm, 5.0 ␮m) Acetonitrile:phosphate buffer pH 3.1 (65:35) C18 (50 x 4.6 mm, 5.0 ␮m) Acetonitrile:methanol (50:50) and ammonium acetate (10 mM, pH 5.5) (90:10)

ESI-MS/MS (m/z 529 → m/z 511)

2.0

n.f.

WAHAJUDDIN et al. (2012) [33]

Halofantrine

WAHAJUDDIN et al., 2015 [27]

KHUDA et al., 2014 [8]

309

Metabolites

L.A. Resende et al. / Journal of Pharmaceutical and Biomedical Analysis 165 (2019) 304–314

Matrix

310

Table 3 (Continued) Metabolites

Sample volume (␮L)

Sample preparation

Solvent/ sorbent

IS

Chromatography

Detection

LOQ (ng/mL)

Recovery (%)

Reference

Human plasma

DLM

200

LLE

Hexane:ethyl acetate (70:30)

Halofantrine

UV (335 nm)

12.5

88.0-102.0

KHALIL et al., 2011 [34]

Human plasma

DLM

100

PPT and SPE

Halofantrine

ESI-MS/MS (m/z 530.2 → m/z 512.4)

2.0

49.7-89.9

SETHI et al., 2011 [35]

Rat plasma

DLM

100

LLE

70.5-80.1

WAHAJUDDIN et al., 2011 [36]

n.a.

100

PPT and SPE

UV (235 nm) and MS/MS (m/z 529 → m/z 511.3) ESI-MS

2.0

Whole blood

Acetonitrile (PPT) and poly(divinyl benzene-co-Nvinylpyrrolidone (SPE) Phosphate buffer (50 mM, pH 3) and n-hexane Acetonitrile: acetic acid (0.5 M) (50:50) (PPT) and C8 (SPE)

Phenyl (250 x 3.0 mm, 4.0 ␮m) Acetonitrile:ammonium acetate buffer (0.1 M, pH 4.9) (85:15) C18 (100 x 2.1 mm, 5.0 ␮m) Acetonitrile:0.1% formic acid in water – gradient elution

200.0 (LOD)

20.0

BLESSBORN et al., 2010 [37]

Human plasma

n.a.

100

PPT

0.5% formic acid in methanol

Piperazine bis chloroquinoline

ESI-MS/MS (m/z 528.2 → m/z 510.3)

220.0

51.5-64.8

MUNJAL et al., 2010 [38]

Rat plasma

n.a.

100

LLE

Phosphate buffer (50 mM, pH 3) and n-hexane

Halofantrine

ESI-MS/MS (m/z 529 → m/z 511.3)

2.0

76.4

WAHAJUDDIN et al., 2009 [39]

Whole blood

DLM

100

LLE

Halofantrine

UV (335 nm)

158.7

45.0-51.0

NTALE et al., 2008 [40]

Whole blood

n.a.

100

SPE

Sodium phosphate buffer (0.4 M, pH 2), potassium hydroxide and diisopropylether C8

TA 3039**

UV (335 nm)

132.2

60.0-65.0

BLESSBORN et al., 2007 [41]

Plasma

n.a.

250

SPE

C8

LUM analogue

UV (335 nm)

25.0

83.0-86.5

ANNERBERG et al., 2005 [42]

Human plasma

DLM

250

SPE

C8

DLM analogue

UV (335 nm)

24.0

63.0-75.0

LINDEGARDH et al., 2005 [43]

Halofantrine

Omitted*

C18 (50 x 4.6 mm, 5.0 ␮m) Acetonitrile:methanol (50:50) and 0.01 M ammonium acetate (pH 4.5) (95:5) C18 (150 x 2.0 mm, 5.0 ␮m) Acetonitrile:ammonium formiate (20 mM with 1.0% formic acid) (5:95) and acetonitrile:ammonium formiate (10 mM with 1% formic acid) (80:20) – gradient elution C8 (50 x 4.6 mm, 5.0 ␮m) Acetonitrile:ammonium acetate buffer (10 mM):0.05% acetic acid (85:10:5) C18 (30 x 2.1 mm, 3.5 ␮m) Acetonitrile-methanol (50:50): ammonium acetate (0.01 M, pH 5.5) (90:10) Phenyl (150 x 4.6 mm, 5.0 ␮m) Acetonitrile:ammonium acetate buffer (0.1 M, pH 6.5) (10:90)

Cyano (150 x 3.0 mm, 3.5 ␮m) Acetonitrile:phosphate buffer (0.1 M, pH 2) (55:45) with sodium perchlorate 0.03 M Cyano (250 x 4.6 mm, 5.0 ␮m) Acetonitrile:phosphate buffer (0.1 M, pH 2) (58:42) with sodium perchlorate 0.01 M Cyano (250 x 4.6 mm) Acetonitrile:phosphate buffer (0.1 M, pH 2) (55:45) with sodium perchlorate 0.05 M

DLM: desbutyl lumefantrine; ESI: electrospray; LLE: liquid-liquid extraction; LOQ: limit of quantification; MIP: molecularly imprinted polymer; MS/MS tandem mass spectrometry; n.a.: not analyzed; PPT: protein precipitation; SPE: solid phase extraction; UV: ultraviolet detector. * Internal standards had no major effect in correcting deviations in the method, therefore the data was omitted (the chromatograms would get less crowded, according to the author). ** Compound structurally similar to lumefantrine.

L.A. Resende et al. / Journal of Pharmaceutical and Biomedical Analysis 165 (2019) 304–314

Matrix

Table 4 Methods for simultaneous determination of ATM and LUM in biological samples. Metabolites

Sample volume (␮L)

Sample preparation

Solvent/ sorbent

IS

Chromatography

Detection

LOQ (ng/mL)

Recovery (%)

Reference

Rat plasma

DHA

50

PPT

Ice-cold methanol containing 0.5% glacial acetic acid and 0.6% hydrogen peroxide

Diazepam

2-ethylpyridine (100 x 3.0 mm, 1.7 ␮m) Carbon dioxide and methanol containing 2 mM ammonium acetate – Gradient elution

2.0 (ATM) 1.0 (LUM)

81.3 (ATM) 81.1 (LUM)

YANG et al., 2018 [46]

Human plasma

n.a

960

PPT

Acetonitrile

n.a

C18 (250 x 4.6 mm, 5.0 ␮m) Methanol: 0.025 M ammonium acetate (38:52)

ESI-MS/MS (m/z 316.4 → m/z 163.1) (ATM) (m/z 530.2 → m/z 512.3) (LUM) UV (216 nm)

600.0 (ATM) 3000.0 (LUM)

SANDHYA et al., 2015 [47]

Human plasma

n.a.

250

PPT

Acetonitrile

Ibuprofen

Human plasma

DHA

n.f.

n.f.

n.f.

Human plasma

n.a.

3000 (ATM) 2000 (LUM) 250

PPT

Acetic acid 0.5% in methanol

Artesunate

C18 (150 x 4.6 mm, 5.0 ␮m) Acetonitrile:methanol: dipotassium orthophosphate buffer (38:42:20) pH 3.0 HPLC (ATM) UHPLC (LUM) Cyano (150 x 4.6 mm, 5.0 ␮m) Methanol: aqueous 10 mM ammonium acetate with 0.2% acetic acid and 0.1% formic acid gradient elution

94.8–98.6 (ATM) 94.3–97.2 (LUM) 96.7-100.5 (ATM) 96.1-103.3 (LUM) n.f.

Human plasma

DHA and DLM

200

PPT

Acetonitrile

TrimipramineD3

C18 (50 x 2.1 mm, 3.0 ␮m) Acetonitrile with 0.5% formic acid: aqueous 20 mM ammonium formate with 0.5% formic acid – gradient elution

UV (220 nm)

300.0 (ATM) 30.0 (LUM)

MS/MS

3.0 (ATM) 50.0 (LUM) 10.0 (both)

ESI-MS/MS (m/z 316.0 → m/z 267.0) (ATM) (m/z 530.0 → m/z 348.0) (LUM) ESI-MS/MS (m/z 221.0 → m/z 163.0) (ATM) ESI-MS/MS (m/z 530.1 → m/z 512.1) (LUM)

5.0 (ATM) 3.0 (LUM)

83.4-88.7 (ATM) 81.4-83.2 (LUM)

86.0-95.3 (ATM) 74.2-89.2 (LUM)

MANNEMALA et al. (2015) [48] LEFÈVRE et al., 2013 [49] CÉSAR et al., 2011 [6]

HODEL et al., 2009 [50]

L.A. Resende et al. / Journal of Pharmaceutical and Biomedical Analysis 165 (2019) 304–314

Matrix

APCI: atmospheric pressure chemical ionization; DHA: dihydroartemisinin; DHAG: dihydroartemisinin-glucuronide; ESI: electrospray; IS: Internal Standard; LLE: liquid-liquid extraction; LOQ: limit of quantification; LPME: liquid-phase microextraction; MS/MS tandem mass spectrometry; n.a.: not analyzed; n.f.: not found; PFP: pentaflourophenyl; PPT: protein precipitation; SPE: solid phase extraction.

311

312

L.A. Resende et al. / Journal of Pharmaceutical and Biomedical Analysis 165 (2019) 304–314

study; appropriate resolution between LUM and halofantrine was observed [23]. Both isocratic and gradient elution have been used. Methanol, acetonitrile or a mixture of them were the organic solvents used in the mobile phase. Lindegardh et al. tested the use of methanol, but observed co-elution between LUM and the internal standard (a compound structurally similar to LUM), employing a cyano column. The use of acetonitrile resulted in satisfactory separation of the peaks. Addition of sodium perchlorate to the mobile phase was found to be efficient for altering the separation between the analytes and interferences. The perchlorate-ion formed an ion pair with the charged analytes increasing their retention while the neutral endogenous compounds remained unaffected [43]. LUM has high molar absorptivity, as a result of aromatic rings and covalent bonds in its chemical structure, making possible the detection with UV spectrophotometry. The wavelength selected in most studies was 335 nm, because a maximum absorption on this wavelength is observed in the spectrum of LUM. Moreover, analysis in 335 nm is more selective than that performed close to 200 nm [45]. All the authors who determined LUM in whole blood used UV detection. Mass spectrometry with ESI in positive ion mode has been utilized for detection in more recent studies. According to the authors, the following transitions were employed for lumefantrine quantification: m/z 528 → m/z 510 and m/z 529 → m/z 511 (each transition used in four methods); m/z 530 → m/z 512; m/z 530 → m/z 347; and m/z 531 → m/z 512 (each transition used in one method). Wahajuddin et al. used tandem mass spectrometry operating in the multiple reaction monitoring (MRM) mode, monitoring the transition of m/z 529 corresponding to [M+H]+ to the product ion m/z 511.3 [39]. The limits of quantification obtained in the methods for LUM determination ranged from 1.0 to 220.0 ng/mL. From the author´s point of view, the analysis of lumefantrine in plasma samples can be carried out suitably employing protein precipitation as sample preparation approach, reversed phase liquid chromatography in the separation step and mass spectrometry for detection. Protein precipitation is a simple and cheap technique able to produce clean extracts. When a more selective approach is required, solid phase extraction can be used. Recently, a molecularly imprinted polymer has been developed for LUM extraction. LUM is an apolar drug (logP 8.7) and reversed phase liquid chromatography is adequate for separation. The use of mass spectrometry is the technique of choice for LUM determination. However, UV detection is an important option, since it is cheaper and simpler than MS, being easier to be applied in pharmacokinetics and therapeutic monitoring in areas with limited resources, where malaria poses a serious issue. 6. Simultaneous determination of artemether and lumefantrine in biological samples The methods published for simultaneous determination of ATM and LUM are presented in Table 4. 6.1. Sample preparation Plasma has been the matrix evaluated in all studies. In all studies published, the technique employed for sample preparation has been protein precipitation. The sample volumes ranged from 50 to 3000 ␮L. The recovery rates were higher than 80% for ATM, and ranged from 74.2 to 103.3% for LUM. Mannemala et al. used 250 ␮L of sample and obtained the highest recovery rates for both drugs [48]. 6.2. Separation and detection Separation has been carried out using reversed phase liquid chromatography in most studies. Recently, Yang et al. developed a

method using supercritical fluid chromatography [46]. C18 or cyano columns were used in liquid chromatography, with 3–5 ␮m particle sizes. Mobile phase was constituted of methanol or acetonitrile as organic solvent and an aqueous acetate, orthophosphate or formate buffer. Both gradient and isocratic elution has been used. Detection has been performed using ESI-MS/MS in most studies. Cesar et al. initially tested ionization by APCI, but obtained an ATM precursor ion [M+H+ ] at a considerably low intensity. Moreover, the method was not able to adequately detect LUM. Therefore, quantitation of ATM was performed using ESI by monitoring the ammonium adduct [M + NH4 ]+ [6]. Sandhya et al. developed a simple method using UV detection. Poor molar absorptivity of ATM presented a significant challenge for simultaneous detection with LUM. The wavelength has been optimized at 216 nm for maximum sensitivity of ATM [47]. The employment of ESI-MS/MS resulted in significantly lower LOQ, compared to UV detection. Limits of quantification ranged from 2.0 to 600.0 ng/mL for ATM, and from 1.0 to 3000.0 ng/mL for LUM. Artesunate, diazepam, ibuprofen and trimipramine-D3 have been used as internal standards. Hodel et al. determined 14 antimalarial drugs in human plasma. Since the authors did not have access to all deuterated analogues or homologues of the drugs, trimipramine-D3 was selected. The authors initially considered using artemisinin as the IS for ATM, but then trimipramine-D3 was found to be suited for artemisinin derivatives. The advantage was the use of only one IS for all 14 drugs investigated in the method [50]. 7. Conclusion Malaria is still a major problem, despite global incidence reduction of 18% between 2010 and 2016. Different strategies, such as vector control, preventive therapies, and appropriate diagnostic testing and treatment, have been applied to reduce the number of cases and deaths related to malaria. Therefore, the use of ACTs, the most effective antimalarial drugs, is essential to reduce the impact of malaria on population. In this context, the monitoring of the analytes concentration is essential to ensure adequate treatment; and cost efficient procedures must be developed continuously. Over the last 18 years, 40 validated methods dealing with quantification of ATM and LUM have been published in the peer-review literature. Most of the methods described presented conventional procedures to collect the samples (venipuncture), extract and concentrate the analytes (protein precipitation, liquidliquid extraction and solid phase extraction with conventional sorbents), and separate the analytes from the interferences (liquid chromatography with 5 ␮m fully porous particle size columns). Therefore, there is still a need to develop more adequate methods, which are rapid, practical, more selective, sensitive, and environmental friendly. Recently, new approaches have been used. Dried blood spot, a procedure commonly used to collect samples from malaria patients in the field, was used in the analysis of LUM. Regarding sample preparation, LPME and SPE with MIP as sorbent, were used to selectively extract ATM and LUM, respectively. Another observed tendency is the employment of faster and sensitive techniques; for example, ultra performance liquid chromatography coupled with mass spectrometry. From the author´s point of view, these methods, still in small numbers, should become more common in the next years. References [1] WHO, Guidelines for the Treatment of Malaria, 3 ed., World Health Organization, Geneva, 2015. [2] WHO, World Malaria Report 2017, World Health Organization, Geneva, 2017.

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