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

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 Abstract

Cyclizine induces cytotoxicity and apoptosis in macrophages through the extrinsic and intrinsic apoptotic pathways

“…19 Cyclizine abuse may lead to various conditions, such as hallucinations, disorientation, confusion, tachycardia, convulsions, facial dyskinesia, complex nutritional problems, and suicide. 3,20,21 Our recent research has demonstrated that cyclizine induces the secretion of proinflammatory cytokines and the expression of inducible nitric oxide synthases through the phosphorylation of nuclear factor-κB and Akt. 22 The adverse effects of cyclizine abuse may be mediated through macrophage dysfunction, which ultimately induces cytotoxicity.…”

“…However, benzhydrylpiperazine derivatives have been demonstrated to induce cytotoxicity in HL‐60 (acute myelocyte leukemia), K‐562 (chronic myeloid leukemia), and SKW‐3 cells (chronic T‐cell leukemia) 19 . Cyclizine abuse may lead to various conditions, such as hallucinations, disorientation, confusion, tachycardia, convulsions, facial dyskinesia, complex nutritional problems, and suicide 3,20,21 . Our recent research has demonstrated that cyclizine induces the secretion of proinflammatory cytokines and the expression of inducible nitric oxide synthases through the phosphorylation of nuclear factor‐κB and Akt 22 .…”

Cyclizine‐induced proinflammatory responses through Akt‐NFκB pathway in macrophages

“…However, cyclizine can be abused for its hallucinogenic and euphoric effects 5 . Bodily responses to overdose and abuse of cyclizine include confusion, tremors, chest pain, ataxia, seizures, and suicidal intentions 6,7 . Evidence has also revealed that adolescents addicted to cyclizine may be at risk of life‐threatening neuromuscular disorders 7 …”

“…5 Bodily responses to overdose and abuse of cyclizine include confusion, tremors, chest pain, ataxia, seizures, and suicidal intentions. 6,7 Evidence has also revealed that adolescents addicted to cyclizine may be at risk of lifethreatening neuromuscular disorders. 7 Macrophages are the primary phagocytes in the immune system.…”

“…6,7 Evidence has also revealed that adolescents addicted to cyclizine may be at risk of lifethreatening neuromuscular disorders. 7 Macrophages are the primary phagocytes in the immune system.…”