Spectrofluorimetric Approach for Quantification of Cyclizine in the Presence of its Toxic Impurities in Human Plasma; in silico Study and ADMET Calculations

Michel Y Fares,Ghada M El-Sayed,Nada S Abdelwahab,Maha A Hegazy,Maha M Abdelrahman

doi:10.1007/s10895-022-02897-3

Michel Y Fares, Ghada M El-Sayed + Show 3 more

Open Access

https://doi.org/10.1007/s10895-022-02897-3

Copy DOI

Abstract

Cyclizine (CYZ); an antiemetic compound; is widely misused for its euphoric or hallucinatory effects, either by oral or intravenous routes. The concomitant abuse of CYZ among addicted adolescents contributes to neuromuscular disorders that are life-threatening. Consequently, with the company of 1-Methylpiperazine (MPZ) and diphenylmethanol (DPM, Benzhydrol) as pharmacopoeia-reported CYZ impurities, a novel spectrofluorimetric assay for the detection of CYZ, has been established either in human plasma samples or in its parenteral formulation. The native fluorescence of CYZ has been investigated under various conditions. Different parameters affecting relative fluorescence intensity of CYZ including diluting solvent, surfactant, plasma protein solvent, and pH were studied and optimized. The linearity obtained between the fluorescence intensity at emission wavelength 350 nm after excitation at 244 nm and the corresponding CYZ concentrations was in the range 10–1000 ng/mL for measurement of CYZ either in pure form or in human plasma samples, with a appropriate correlation coefficient (r = 0.9999) and 3.10 ng/mL as the limit of detection and 9.41 ng/mL as the limit of quantitation. The suggested procedure was created and validated in accordance with ICH guidelines for quantification of CYZ either in its pure form or its dosage form, and FDA guidelines for the assay of CYZ in human plasma. Finally, in silico study and ADMET predictions were conducted for the studied drug impurities to estimate their pharmacokinetic behaviors. The results showed that both CYZ impurities have higher cellular permeability and maximum tolerated doses, DPM has higher BBB and CNS permeability than MPZ, while MPZ exceeds DPM in total clearance and volume of distribution.Graphic

Highlights

Cyclizine (CYZ), 1-benzhydryl-4-methylpiperazine or 1-(diphenylmethyl)-4-methylpiperazine, is a piperazine derivative which has been competently indicated for the preclusion and therapy for nausea and vomiting linked to motion sickness Fig. 1 [1]
Many cases of CYZ dependency were found in people with conventional types of recreational drug abuse, but long-term opiates are reported in patients with chronic pain of uncertain origin
Spectrofluorimetric method has many advantages like great sensitivity, selectivity, reduced light-scattering interference, rapidity, easiness of spectral complexity, and quite low prices [26]. It has a linear response over a broad concentration range and high flexibility, owing to the ability to choose both the emission and excitation wavelengths, and to analyze samples in both solid and liquid states [30]

Summary

Introduction

Cyclizine (CYZ), 1-benzhydryl-4-methylpiperazine or 1-(diphenylmethyl)-4-methylpiperazine, is a piperazine derivative which has been competently indicated for the preclusion and therapy for nausea and vomiting linked to motion sickness Fig. 1 [1]. Teenagers or patients with cancer in the inpatient unit of major cancer centers have misused CYZ in large doses intravenously (IV) [4]. Many cases of CYZ dependency were found in people with conventional types of recreational drug abuse, but long-term opiates are reported in patients with chronic pain of uncertain origin. Abuse of CYZ has been documented for more than 40 years, but these concerns are not commonly recognized [5]. The most frequently described symptoms were confusion, hallucinations, disorientation, tremors, drowsiness, dysarthria, chest pain, ataxia, seizures, as well as lead to suicide [6]

Objectives

Methods

Results

Conclusion