Metopimazine Research Articles

A new spectrophotometric method for the quantitative determination of Metopimazine based on the absorbance of its sulfoxide

Metopimazine (MPZ) is a dopamine antagonist from the phenothiazine class of drugs. It has antiemetic properties and is used to treat nausea and vomiting, including those associated with cancer chemotherapy. We have proposed a new method for the quantitative determination of Metopimazine by spectrophotometry. The drug is determined using a difference spectrophotometric technique based on the absorbance of its previously prepared sulfoxide derivative (λmax = 355 nm, ε = 4.5 × 103 L/mol cm) relative to a solution of a non-derivatised drug. The sulfoxide derivative is formed quickly and quantitatively at room temperature by adding potassium caroate solution. The difference in the absorbance of solutions at 355 nm is proportional to the concentration of MPZ in the drug. The method is specific for an intact drug in the presence of oxidative and photochemical decomposition products and excipients. The linearity range is 0.9–30.0 μg/mL. Regression line equation: ΔA = 0.0061 × c (r = 0.999), where c is the MPZ concentration in μg/mL. The limit of quantitation, LOQ (10S), is 2.8 μg/mL. The possibility of quantitative determination of MPZ content in the bulk drug and tablets of Vogalen Lyok 7.5 mg with a relative standard deviation of 1.21% (δ = + 0.05%) and 1.38% (δ = – 0.67%), respectively, was shown. │δ│ < tα (0.95, n = 7) × RSD/√n, where δ = (x¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{x}$$\\end{document}–μ) × 100%/μ (μ—quantification data, given in the Certificate of Quality).

Metopimazine is primarily metabolized by a liver amidase in humans.

Metopimazine (MPZ) is a peripherally restricted, dopamine D2 receptor antagonist used for four decades to treat acute nausea and vomiting. MPZ is currently under clinical investigation for the treatment of gastroparesis (GP). MPZ undergoes high first‐pass metabolism that produces metopimazine acid (MPZA), the major circulating metabolite in humans. Despite a long history of use, the enzymes involved in the metabolism of MPZ have not been identified. Here we report a series of studies designed to identify potential MPZ metabolites in vitro, determine their clinical relevance in humans, and elucidate the enzymes responsible for their formation. The findings demonstrated that the formation of MPZA was primarily catalyzed by human liver microsomal amidase. Additionally, human liver cytosolic aldehyde oxidase (AO) catalyzes the formation of MPZA, in vitro, although to a much lesser extent. Neither cytochrome P450 enzymes nor flavin‐monooxygenases (FMO) were involved in the formation MPZA, although two minor oxidative pathways were catalyzed by CYP3A4 and CYP2D6 in vitro. Analysis of plasma samples from subjects dosed 60 mg of MPZ verified that these oxidative pathways are very minor and that CYP enzyme involvement was negligible compared to microsomal amidase/hydrolase in overall MPZ metabolism in humans. The metabolism by liver amidase, an enzyme family not well defined in small molecule drug metabolism, with minimal metabolism by CYPs, differentiates this drug from current D2 antagonists used or in development for the treatment of GP.

Pharmacokinetic study of metopimazine by oral route in children.

Metopimazine (MPZ) is an antiemetic considered as a currently used drug. In France, it has become the leading antiemetic mediator due to its good tolerance, however, its pharmacokinetics has never previously been studied in children. MPZ was administered by oral route to 8 children with a single dose of 0.33 mg/kg during an endocrine exploration using stimuli well known for its adverse emetic effects. We used biological remnants from sera following an hGH test in order to obtain the MPZ pharmacokinetics. Plasmatic concentrations of MPZ and the active acid metabolite AMPZ, were quantified by HPLC-MS/MS during a 270 min test period. MPZ is quickly absorbed with a median Cmax of 17.2 ng/mL at one hour and its half-life is 2.18 h. The plasmatic concentrations of AMPZ were higher than MPZ with a median Cmax of 76.3 ng/mL, a Tmax to 150 min and its concentration was approximately maintained at 50 ng/mL from 1 to 4 h. The plasmatic concentrations in children are similar to those observed in adults. No adverse effects, nausea or vomiting occurred during the trial. Therefore, these results confirm the MPZ dosage that should be used in children under 15 kg administered as 0.33 mg/kg up to 3 times a day.

Stability indicating HPTLC method for determination of Metopimazine in pharmaceutical formulation and human plasma

Accurate, selective and sensitive stability indicating high performance thin layer chromatographic (HPTLC) method was developed and validated for determination of Metopimazine (MPZ) in presence of its degradation products; including the oxidative degradation product (Deg I) and the alkaline hydrolysis degradation product (Deg II; formerly reported as acid metabolite). The proposed method was applied for analysis of MPZ in pure form, pharmaceutical formulation (tablets) and human plasma over the concentration range of 0.4–1.4 μg band−1 with accuracy of mean percentage recovery 100.10 ± 0.941. The method depends on separation of MPZ from its degradation products on HPTLC silica gel 60 F254 plates using chloroform–methanol–ammonia (12:2:0.1, by volume) as developing system followed by densitometric measurement of bands at 254 nm. The method was validated according to ICH guidelines. The degradation products were well resolved from the pure drug with significantly different Rf values (MPZ, Rf = 0.58, Deg I, Rf = 0.35 and Deg II, Rf = 0.03). The results obtained by the proposed method were statistically compared to the reported HPTLC method, and there was no significant difference between them regarding both accuracy and precision; indicating the ability of the proposed method to be used for routine analysis of drug product.

Fragmentation pathways of metopimazine and its metabolite using ESI‐MSn, HR‐MS and H/D exchange

Metopimazine (MPZ) is a phenothiazine derivative used to prevent emesis during chemotherapy where few structural analysis of the aforementioned compound have been described in the literature. Thus, this work reports, for the first time, the detailed study of fragmentation pathways of MPZ and its metabolite (AMPZ) using electrospray ionization (EI) with multistage mass spectrometry (ESI-MS(n)) in positive-ion mode. The structures of 21 product ions were identified and their accurate masses were determined using high resolution mass spectrometry (HRMS) experiments. Characteristic product ions of these two phenothiazine derivatives are more particularly displayed along with differences between their relative abundances and their structures checked by H/D exchange experiments.

Percutaneous Absorption of Metopimazine and Effect of Cyclodextrins

Metopimazine (MPZ) is used to prevent emesis during chemotherapies. A transdermal delivery system of MPZ may present a great advantage in patients to improve compliance. Hydroxypropyl β cyclodextrin (HPβCD) and partially methylated β cyclodextrin (PMβCD) were tested to enhance the percutaneous absorption of MPZ through pig skin using Franz's cells. The MPZ hydrochloride flux was low with 0.176 ± 0.054 μg/h/cm2 and no flux was detected with a suspension of MPZ (base). The used characterization analyses demonstrated the formation of an inclusion complex with cyclodextrin and this complex improved percutaneous absorption of MPZ. Flux was increased to 0.240 ± 0.032 μg/h/cm2 and 0.566 ± 0.057 μg/h/cm2 for HPβCD and PMβCD, respectively, with a concentration of 20%. This study has shown that HPβCD and PMβCD improved the percutaneous penetration of MPZ. Cyclodextrin complexes increased MPZ bioavailability at the skin surface and PMβCD was also able to extract cutaneous fatty acids.

Effect of partially methylated β cyclodextrin on percutaneous absorption of metopimazine

Metopimazine (MPZ) is an antiemetic drug used by oral and rectal administration. A transdermal delivery system of MPZ may present a great advantage for the treatment of nausea and vomiting to improve therapeutic adhesion. MPZ is a lipophilic drug with poor water solubility. Partially methyled β cyclodextrin (PMβ-CD) was tested to enhance percutaneous absorption of MPZ. Complex MPZ/cyclodextrin was characterized by Higushi’s phase solubility, Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) analyses and MPZ octanol partition coefficient was also determinated. The permeation of free MPZ and inclusion complex through pig skin were investigated using Franz’s cells. Four concentrations of cyclodextrins, 0, 5, 10 and 20% were tested. Partition coefficient was depending on pH of the solution. At pH 5.5, MPZ ionization increased the hydrophily (0.71) and at pH 10.3, non-ionized MPZ was the dominant form (591). The solubility of MPZ increased with the concentration of PMβ-CD and the phase solubility diagram is an Ap type. The used characterization analyses demonstrated the formation of an inclusion complex and this complex improved percutaneous absorption of MPZ. No MPZ flux was detected for a suspension of MPZ and it was more important with MPZ hydrochloride, 0.177 ± 0.044 μg/h/cm². Flux was increased to 0.570 ± 0.058 μg/h/cm² with a concentration of 20%. The use of cyclodextrin with MPZ hydrochloride increased also the percutaneous absorption with 0.549 ± 0.175 μg/h/cm² for a concentration of 5%, 0.435 ± 0.031 μg/h/cm² for a concentration of 10% and 0.474 ± 0.054 μg/h/cm² for a concentration of 20%. This study shows that PMβ-CD improves percutaneous penetration of MPZ. But the absorption is not enough to allow a therapeutic effect. Cyclodextrin complex increases MPZ solubility and this bioavailability at the skin surface, and cyclodextrin may also modify the barrier propriety of skin.

Differential pulse cathodic voltammetric determination of floctafenine and metopimazine

A simple, rapid and sensitive voltammetric method for the determination of floctafenine (FFN) and metopimazine (MPZ) was developed. Well-defined cathodic waves were obtained for both drugs in Britton–Robinson buffer pH 9.0 using the differential-pulse mode at the hanging mercury drop electrode (HMDE). The current–concentration relationship was found to be linear over the ranges 0.4–3.6 and 0.4–2.4 μg ml −1 for FFN and MPZ, respectively. The quantification of the two drugs in their pharmaceutical formulations was carried out using the proposed voltammetric method and compared with spectrophotometric analysis data. The mechanisms of the electrode reactions for the two drugs were proposed.

Metopimazine eases the queaze in delayed emesis

Metopimazine eases the queaze in delayed emesis

Metopimazine easing in emesis

Metopimazine easing in emesis

Metopimazine easing in emesis

Metopimazine easing in emesis

The efficacy of a combination of ondansetron, methyiprednisolone and metopimazine in patients previously uncontrolled with a dual antiemetic treatment in cisplatin-based chemotherapy

Cisplatin is one of the most effective cytotoxic drugs used in the treatment of certain neoplasms, but is also one which most frequently induces nausea and vomiting. Combination of corticosteroids with ondansetron enables greater control of emesis than that obtained with ondansetron alone, but some patients still experience symptoms. The objective of this randomised, double-blind, multicentre, parallel group study was to examine the benefit of the addition of metopimazine (MPZ), a dopamine receptor antagonist, to the combination of ondansetron + methylprednisolone (O + M) in the prevention of cisplatin-induced nausea and vomiting in patients uncontrolled [i.e., at least one emetic episode (vomiting and/or retching) or moderate or severe nausea] during their previous course of cisplatin based chemotherapy, despite antiemetic treatment with a combination of a 5-hydroxytryptamine3 receptor antagonist (5HT3) with a corticosteroid. The impact of the treatment on the patients' quality of life was also evaluated using two specific questionnaires the FLIC (Functional Living Index for Cancer), and the FLIE (Functional Living Index for Emesis). The intent-to-treat population consisted of 338 patients; 168 patients received the triple combination of ondansetron, methylprednisolone and metopimazine (O + M + MPZ), and 170 patients received ondansetron plus methylprednisolone (O + M). Tumour type was comparable in the two treatment groups, the most prevalent being lung cancer. Patients in group O + M + MPZ received ondansetron as an 8 mg intravenous injection prior to chemotherapy on day 1 followed by 8 mg tablets b.i.d. from D2 to D3, methylprednisolone as a 120 mg intravenous injection prior to chemotherapy on D1 and followed by 16 mg tablets b.i.d. from D2 to D3, and metopimazine as a 40 mg intravenous injection prior to chemotherapy on D1 and followed by 15 mg capsules b.i.d. on D2 to D3. Patients in group O + M received treatment with ondansetron and methylprednisolone as above. Analysis of the primary efficacy criterion (absence of emetic episode throughout the course of chemotherapy) revealed a success rate of 53% in the group receiving O + M + MPZ and 38% in the group receiving O + M (P = 0.008). Analysis of the secondary efficacy criteria (nausea grade, number of emetic episodes and global patient satisfaction on D1 and from D2 to D3) showed a statistically significant difference between the two groups, in favour of the O + M + MPZ treatment. The scores obtained with the FLIC and FLIE questionnaires did not reveal any significant differences between the two groups. Treatment was well tolerated in both groups. The study showed that the addition of MPZ to the combination O + M was an effective and well tolerated antiemetic treatment, with a 15% increase in efficacy compared to the combination in patients not controlled during their previous course of chemotherapy. The addition of metopimazine to existing regimens containing 5HT3 receptor antagonist and steroid combination should be considered for patients who fail on their previous course.

Bioavailability of the antiemetic metopimazine given as a microenema

The absorption of the antiemetic metopimazine (MPZ) given as a single dose of (a) 40 mg microenema, (b) 40 mg orally and (c) 10 mg as a 60 min i.v. continuous infusion was investigated in six healthy volunteers. Blood samples were drawn and the serum concentrations of MPZ and its acid metabolite were measured. The bioavailability of MPZ given orally and as enemas was 22.3 and 19.5% respectively. Partial avoidance of hepatic first pass metabolism was seen with the enemas, which in contrast to suppositories, seems to represent a reliable form of rectal administration.

Interaction of the antiemetic metopimazine and anticancer agents with brain dopamine D2, 5-hydroxytryptamine3, histamine H1, muscarine cholinergic and ?1 receptors

The interactions of the antiemetic metopimazine (MPZ) and of the chemotherapeutic agents, cisplatin, carboplatin, doxorubicin, etoposide and vincristine were investigated at five neurotransmitter receptor binding sites. MPZ had nanomolar affinity for alpha 1, dopamine D2 and histamine H1 receptors, weak affinity for muscarinic cholinergic receptors, but no affinity for 5-hydroxytryptamine3 (5-HT3) receptors. Except for vincristine, which showed nanomolar affinity of muscarinic cholinergic receptors, none of the chemotherapeutic agents showed affinity for any of the receptors investigated at concentrations ranging between 10(-5) and 10(-7) M. Accordingly, chemotherapy-induced nausea and vomiting seems to be mediated by mechanisms other than the direct interaction of cytostatics with the neurotransmitter receptors investigated. Our finding that MPZ is without affinity for 5-HT3 receptors and therefore seems to mediate its antiemetic effect predominantly by dopamine D2 receptor blockade makes it an interesting drug for use in combinations with the new class of antiemetics, the 5-HT3 receptor antagonists. Data obtained in a recent clinical trial support this observation.

The effect of food on serum concentrations of metopimazine.

1. Six healthy volunteers were given single oral doses of the antiemetic metopimazine (MPZ), starting with trial (a) 20 mg preprandially and followed by trial (b) 50 mg preprandially. In trials (c) and (d) the doses were similar to those in trials (a) and (b), but MPZ was given postprandially. To evaluate intra-individual variation in serum concentrations, trial (a) was repeated three times in four of the volunteers (trial (e)). 2. Blood samples were drawn and the serum concentrations of MPZ and its acid metabolite (AMPZ) were measured by h.p.l.c. 3. There was no evidence of dose-dependent kinetics at the dose levels studied. 4. Median AUC values were 22.6, 16.2, 52.4 and 35.2 (trials (a), (b), (c) and (d), ng ml-1 h). Food intake decreased the serum concentrations of MPZ, suggesting that MPZ should be taken preprandially.