Blood and Urine Concentrations of Cyclizine by Nitrogen-Phosphorus Gas-Liquid Chromatography

Griffin, D.S.; Baselt, Randall C.

doi:10.1093/jat/8.2.97

Cited by 16 publications

(4 citation statements)

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“…The concentrations of CYC found in the serum of the subject used in this study, in which only a 200 l sample was used are similar to those obtained in human studies in which the peak concentrations in plasma and serum after oral administration were 69 ng/ml [7] and 80 g/ml using a 2 ml serum aliquot [8] and 57 ng/ml using a 1 ml sample [11].…”

Section: Resultssupporting

confidence: 81%

“…Assay methods for CYC in both serum and urine have used colorimetric detection methods [4], derivatization with tritiated acetic anhydride [5], gas-liquid chromatography [6,7], GC-MS [8,9] and HPLC with ultraviolet detection [10,11]. Limitations of some of these methods include the lack of the requisite sensitivity and selectivity necessary for accurate assessment of the pharmacokinetics of the drug.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An LC–MS–MS method for the determination of cyclizine in human serum

Mohammadi¹,

Kanfer²,

Sewram³

et al. 2005

Journal of Chromatography B

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Section: Resultssupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

An LC–MS–MS method for the determination of cyclizine in human serum

Mohammadi¹,

Kanfer²,

Sewram³

et al. 2005

Journal of Chromatography B

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“…Using pharmacokinetic and pharmacodynamic (PK/PD) data from past clinical trials, we evaluated the potential for the 1 st generation antihistamines to be repurposed without modification. The typical adult dosing regimens for diphenhydramine, chlorcyclizine and related compounds is one 25/50/100 mg tablet 2–4 times per day(Blyden, Greenblatt, Scavone, & Shader, 1986; Fouda, Hobbs, & Stambaugh, 1979; Griffin & Baselt, 1984; Labout, Thijssen, Keijser, & Hespe, 1982). The maximum plasma concentration (Cmax) for the maximum recommended doses of these compounds in adults is on average 100 ng/L which is significantly lower than our reported IC50’s between >1 μM(Blyden et al, 1986; Fouda et al, 1979; Griffin & Baselt, 1984; Labout et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

Repurposing potential of 1st generation H1-specific antihistamines as anti-filovirus therapeutics

et al. 2018

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Ebola and Marburg are filoviruses and biosafety level 4 pathogens responsible for causing severe hemorrhagic fevers in humans with mortality rates up to 90%. The most recent outbreak in West Africa resulted in approximately 11,310 deaths in 28,616 reported cases. Currently there are no FDA-approved vaccines or therapeutics to treat infections of these deadly viruses. Recently we screened an FDA-approved drug library and identified numerous G protein-coupled receptor (GPCR) antagonists including antihistamines possessing anti-filovirus properties. Antihistamines are attractive targets for drug repurposing because of their low cost and ease of access due to wide use. In this report we identify common over the counter antihistamines, such as diphenhydramine (Benadryl) and chlorcyclizine (Ahist) as potential candidates for repurposing as anti-filovirus agents. Furthermore, we demonstrate that this potential is wide-spread through the 1st generation of H-specific antihistamines but is not present in newer drugs or drugs targeting H, H and H receptors. We showed that the filovirus entry inhibition is not dependent on the classical antagonism of cell surface histamine or muscarinic acetylcholine receptors but occurs in the endosome, like the cathepsin inhibitor CA-074. Finally, using extensive docking studies we showed the potential for these drugs to bind directly to the EBOV-GP at the same site as toremifene. These findings suggest that the 1st generation antihistamines are excellent candidates for repurposing as anti-filovirus therapeutics and can be further optimized for removal of unwanted histamine or muscarinic receptor interactions without loss of anti-filovirus efficacy.

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“…Solid-phase cationexchange extraction of basic drugs from greyhound urine has been described (Moore 1990). The determination of cyclizine and norcyclizine in biological¯uids by gas±liquid chromatography with nitrogen-selective detection (Land et al 1981, Gri n andBaselt 1984) and high-performance liquid chromatography with coulometric detection (Walker and Kanfer 1995) has also been reported. The importance of tissue and plasma protein binding in the retention of norcyclizine in man, dog and rat has also been reported (Kuntzman et al 1967).…”

mentioning

confidence: 99%

Biotransformation of cyclizine in greyhounds. 1: identification and analysis of cyclizine and some basic metabolites in canine urine by gas chromatography-mass spectrometry

Dumasia¹,

Grainger²,

Houghton³

2002

Xenobiotica

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1. The partial in vivo biotransformation of Marezine [(cyclizine.HCl); 1-diphenylmethyl-4-methylpiperazine hydrochloride] in the racing greyhound and the excretion of the unconjugated and conjugated (Phase II) basic metabolites of cyclizine in canine urine are reported. 2. Using copolymeric bonded mixed-mode solid-phase extraction cartridges, the basic isolates from both unhydrolysed and enzyme hydrolysed urine samples were isolated, derivatized as trimethylsilyl ethers and analysed by positive-ion electron ionization gas chromatography-mass spectrometry (EI(+)-GC-MS). Selected samples were analysed by positive-ion methane chemical ionization (CI(+))-GC-MS to aid structure elucidation of the putative metabolites. 3. Cyclizine was the major component excreted in post-administration urine. Five substrate-related basic compounds (M1--> M5) were tentatively identified by EI(+)- and CI(+)-GC-MS. The major Phase I metabolite was identified as norcyclizine [1-diphenylmethylpiperazine] (M1), the other metabolites (M2 --> M5) were tentatively identified as monohydroxylated products based on MS data. 4. Cyclizine and the N(4)-desmethyl metabolite (M1) are excreted unconjugated; the other four hydroxylated metabolites are excreted as Phase II conjugates (glucuronides and/or sulphates). Structures of the putative basic metabolites are presented. At least four other basic metabolites were also detected in post-administration urine, but could not be characterized from GC-MS data. 5. All unhydrolysed post-administration urine samples were analysed by selected ion monitoring EI(+)-GC-MS to quantify cyclizine and norcyclizine (M1) using authentic cyclizine as the analyte and chlorcyclizine as the internal standard. The level of M1 is expressed as 'cyclizine equivalents'. The duration of urinary elimination of cyclizine and M1 was obtained from their excretion profiles. 6. From these studies, cyclizine and norcyclizine (M1) would be the target compounds of choice in the development of screening and confirmatory methods for the detection of cyclizine administration to racing greyhounds. Information on any of the other metabolites may also be of some value for confirmatory analysis.

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Blood and Urine Concentrations of Cyclizine by Nitrogen-Phosphorus Gas-Liquid Chromatography

Cited by 16 publications

References 0 publications

An LC–MS–MS method for the determination of cyclizine in human serum

An LC–MS–MS method for the determination of cyclizine in human serum

Repurposing potential of 1st generation H1-specific antihistamines as anti-filovirus therapeutics

Biotransformation of cyclizine in greyhounds. 1: identification and analysis of cyclizine and some basic metabolites in canine urine by gas chromatography-mass spectrometry

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