Ultra‐fast chromatographic micro‐assay for quantification of diphenidol in plasma: application in an oral multi‐dose switchability trial

Marcelín‐Jiménez, Gabriel; Morales-Martínez, Miriam; Ángeles-Moreno, Alionka P.; Mendoza‐Morales, Luís

doi:10.1002/bmc.1037

Cited by 9 publications

(1 citation statement)

References 1 publication

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“…The method was adapted from that of MarcelinJimanez et al (32). The mass spectrometer was operated in the positive ionization mode using electrospray (ESI) ionization under the following conditions: spray voltage of 4,800 V, sheath gas (nitrogen) flow of 35 (arbitrary units), capillary temperature of 370°C with argon as the collision gas at a pressure of 0.8 mtorr.…”

Section: Mass Spectroscopymentioning

confidence: 99%

Multiple mechanisms of ligand interaction with the human organic cation transporter, OCT2

Harper

Wright

2013

American Journal of Physiology-Renal Physiology

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OCT2 is the entry step for organic cation (OC) secretion by renal proximal tubules. Although many drugs inhibit OCT2 activity, neither the mechanistic basis of their inhibition nor their transport status is generally known. Using representatives of several structural classes of OCT2-inhibitory ligands described recently (Kido Y, Matsson P, Giacomini KM. J Med Chem 54: 4548-4558, 2011), we determined the kinetic basis of their inhibition of 1-methyl-4-phenylpyridinium (MPP) transport into Chinese hamster ovary cells that stably expressed hOCT2. The "cluster II" inhibitors (which contain known OCT2 substrates) metformin and cimetidine interacted competitively with MPP. However, other cluster II compounds, including tetraethylammonium (TEA), diphenidol and phenyltoloxamine, were mixed-type inhibitors of MPP transport (i.e., decreasing J(max) and increasing K(t)). A cluster III (neutral steroid) representative, adrenosterone, and a cluster I (large, flexible cation) representative, carvedilol, displayed noncompetitive inhibitory profiles. Competitive counterflow (CCF) was used to determine whether the inhibitory ligands served as substrates of hOCT2. Carvedilol (cluster I) and adrenosterone (cluster III) did not support CCF, consistent with the prediction that members of these structural classes are likely to be nontransported inhibitors of OCT2. The cluster II representatives MPP, metformin, cimetidine, and TEA all supported CCF, consistent with independent assessments of their OCT2-mediated transport. However, the other cluster II representatives, diphenidol and phenyltoloxamine, failed to support CCF, suggesting that neither compound is transported by OCT2. An independent assessment of diphenidol transport (using liquid chromatography with tandem mass spectroscopy) confirmed this observation. The results underscore the caution required for development of predictive models of ligand interaction with multidrug transporters.

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Section: Mass Spectroscopymentioning

confidence: 99%

Multiple mechanisms of ligand interaction with the human organic cation transporter, OCT2

Harper

Wright

2013

American Journal of Physiology-Renal Physiology

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Identifying metabolites of diphenidol by liquid chromatography‐quadrupole/orbitrap mass spectrometry using rat liver microsomes, human blood, and urine samples

Yang

Zhao²,

Liu³

et al. 2021

Drug Testing and Analysis

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In recent years, diphenidol [1,1-diphenyl-4-piperidino-1-butanol] has been one of the drugs that appears in suicide cases, but there are few research data on its metabolic pathways and main metabolites. Metabolite identification plays a key role in drug safety assessment and clinical application. In this study, in vivo and in vitro samples were analyzed with ultra-high-performance liquid chromatographyquadrupole/electrostatic field orbitrap high-resolution mass spectrometry. Structural elucidation of the metabolites was performed by comparing their molecular weights and product ions with those of the parent drug. As a result, 10 Phase I metabolites and 5 glucuronated Phase II metabolites were found in a blood sample and a urine sample from authentic cases. Three other Phase I metabolites were identified in the rat liver microsomes incubation solution. The results showed that the main metabolic

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Fatal diphenidol poisoning: a case report and a retrospective study of 16 cases

Zhang

Li³

et al. 2015

Forensic Sci Med Pathol

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Diphenidol hydrochloride (DPN), a nonphenothiazinic antiemetic agent used primarily in patients with Meniere disease and labyrinthopathies to treat vomiting and vertigo, is considered to be a relatively safe drug. Since it was first approved in the United States in 1967, this drug has been widely used in Latin America and Asia and has contributed to sporadic suicidal and accidental poisonings in mainland China and Taiwan. However, its toxic or lethal concentration ranges have not yet been determined. We report a case of a 23-year-old female who suffered from DPN poisoning that resulted in death. At autopsy, there were no typical pathological findings, except for cerebral edema with high acetylcholinesterase expression. Postmortem analysis of DPN revealed 45 µg/ml in heart blood, 39 µg/ml in femoral vein blood, 141 µg/g in the liver, and 53 mg in the gastric contents. These concentrations indicated that the cause of death was DPN poisoning. The circumstances indicated that the manner of death was suicide. We also present a retrospective study, in which we review and summarize the literature from 1998 to 2014 and describe 16 cases of poisoning, including information from autopsy reports and postmortem drug concentrations. In forensic practice, drug residues at the scene, patients with convulsions and disturbance of consciousness, and rapidly occurring deaths, should draw attention to the possibility of this drug. Toxicological analysis and the exclusion of other diseases may ultimately be used to confirm DPN poisoning.

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Ultra‐fast chromatographic micro‐assay for quantification of diphenidol in plasma: application in an oral multi‐dose switchability trial

Cited by 9 publications

References 1 publication

Multiple mechanisms of ligand interaction with the human organic cation transporter, OCT2

Multiple mechanisms of ligand interaction with the human organic cation transporter, OCT2

Identifying metabolites of diphenidol by liquid chromatography‐quadrupole/orbitrap mass spectrometry using rat liver microsomes, human blood, and urine samples

Fatal diphenidol poisoning: a case report and a retrospective study of 16 cases

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