Rapid and efficient purification of cimetropium bromide and mifentidine drug metabolite mixtures derived from microsomal incubates for analysis by mass spectrometry

Kajbaf, M.; Jahanshahi, M.; Pattichis, K.; Gorrod, J. W.; Naylor, Stephen

doi:10.1016/0378-4347(92)80506-l

Cited by 20 publications

(6 citation statements)

References 24 publications

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“…SKF 525-A, DPEA, and methimazole also had an inhibitory effect on the formation of M4 reducing the levels to 61%, 78% and 61% of control values, respectively. MSIMS studies con finned that daughter ion spectra of ions derived from the above-mentioned metabolites were identical to daughter ion spectra derived from authentic amine, fonnamide, urea and i-OH-amine (6)(7)(8)(9)(10). It was shown that the formamide can undergo further hydrolysis to the amine by incubating the formamide in the presence of microsomes.…”

Section: Resultsmentioning

confidence: 95%

“…For induction studies, male rabbits were pretreated as follows: Incubation, extraction and analytical procedures were as described previously (6)(7)(8)(9)(10). Extraction was carried out using either acetonitrile (3 x 3 ml) in the presence of sodium chloride, or Sep-Pak CI8 cartridges (Waters Chromatography Division, Millipore UK, Harrow, UK).…”

Section: Methodsmentioning

confidence: 99%

“…Previous work carried out by us (6)(7)(8)(9) has shown that mifentidine is metabolised to seven metabolites, namely 4-imidazolylphenylamine ('amine'), 4-imidazolylphenylformamide ('formamide'), the urea derivative of mifentidine ('urea'), and the imidazolehydroxylated derivative of the 4-imidazolylphenylamine ('i-OH-amine'), together with three unidentified metabo- (6)(7)(8)(9). *Not identified in hepatic microsomal incubates in this work.…”

Section: Introductionmentioning

confidence: 99%

“…Ziegler (University of Texas, Austin, TX, USA). All other materials used were as previously described (6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

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In vitro studies on the metabolic fate of mifentidine, a novel histamine H2-receptor antagonist

Pattichis

Kajbaf

Gorrod

1997

European Journal of Drug Metabolism and Pharmacokinetics

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The in vitro metabolism of mifentidine and several of its metabolites was studied using hepatic microsomes from seven animal species. The effects of potential enzyme inducers, inhibitors and activators were also studied. Mifentidine metabolites identified and characterised were: 4-imidazolylphenylamine (amine), 4-imidazolylphenyl-formamide (formamide), the urea derivative of mifentidine (urea) and the imidazole-hydroxylated derivative of the amine (i-OH-amine), along with three unidentified metabolites, M1, M2 and M3. Evidence for the presence of the amine, formamide, urea and i-OH-amine was obtained by comparison with authentic reference compounds: (i) HPLC retention times; (ii) UV spectra; and (iii) MS spectra of metabolites. The postulated intermediates are: carbinolimine (for formamide, amine, i-OH-amine and urea formation); formamide (for amine and i-OH-amine formation); amine (for i-OH-amine formation), and nitrone (for urea formation). One 'metabonate' of mifentidine was also identified, namely the nitro analogue of the amine. A possible prerequisite for the formation of this nitro is the corresponding hydroxylamine or nitroso compound. Cytochromes P450I and P450II were shown to be involved in the in vitro microsomal biotransformation of mifentidine, but the involvement of the flavin monooxygenase system was not proven.

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Section: Resultsmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Ziegler (University of Texas, Austin, TX, USA). All other materials used were as previously described (6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

In vitro studies on the metabolic fate of mifentidine, a novel histamine H2-receptor antagonist

Pattichis

Kajbaf

Gorrod

1997

European Journal of Drug Metabolism and Pharmacokinetics

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“…Earlier publications have described methods of cimetro pium analysis in biological samples using high-performance liquid chromatography(HPLC) 7,8 and mass spectrometry. 9 However, these methods suffer from a number of disadvantages, including insufficient sensitivity (lower limit of quantification (LLOQ) up to 2 ng ml 1 ) and the need for extensive sample preparation and large biological fluid volumes (up to 1 ml of plasma). Moreover, the sensitivities of these methods are generally inadequate for studies involving low oral doses or for the topical formulations currently under development.…”

Section: Cimetropium Bromide [8-(cyclopropylmethyl)-6ˇ7ˇ-epoxy-3˛-hymentioning

confidence: 99%

A rapid and sensitive liquid chromatography/positive ion tandem mass spectrometry method for the determination of cimetropium in human plasma by liquid–liquid extraction

Lee¹,

Park²,

Kim³

et al. 2006

J. Mass Spectrom.

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We have developed and validated a simple detection system with high-performance liquid chromatography (HPLC) with positive ion electrospray ionization tandem mass spectrometry (ESI-MS/MS) for determining cimetropium levels in human plasma using scopolamine butyl bromide as an internal standard (I.S.). The acquisition was performed in the multiple reaction monitoring (MRM) mode, by monitoring the transitions: m/z 357.9 > 103.1 for cimetropium and m/z 359.9 > 103.1 for butyl-scopolamine. The method involves a simple single-step liquid-liquid extraction with dichloromethane. The analyte was chromatographed on an YMC C18 reversed-phase chromatographic column by isocratic elution with 10 mM ammonium formate buffer-methanol (19:81, v/v; adjusted to pH 4.0 with formic acid). The results were linear over the studied range (0.2-100 ng ml(-1)), with r2 = 1.0000, and the total analysis time for each run was 2 min. Intra- and interassay precisions were 0.70-8.54% and 1.08-4.85%, respectively, and intra- and interassay accuracies were 97.56-108.23% and 97.48-103.91%, respectively. The lower limit of quantification (LLOQ) was 0.2 ng ml(-1). At this concentration, mean intra- and interassay precisions were 8.54% and 4.85%, respectively, and mean intra- and interassay accuracies were 97.56% and 98.91%, respectively. The mean recovery ranged from 62.71 +/- 4.06 to 64.23 +/- 2.32%. Cimetropium was found to be stable in plasma samples under typical storage and processing conditions. The devised assay was successfully applied to a pharmacokinetic study of cimetropium bromide administered as a single oral dose (150 mg) to healthy volunteers.

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An evaluation of tandem mass spectrometry in drug metabolism studies

Naylor

Kajbaf

Lamb

et al. 1993

Biol. Mass Spectrom.

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The use of precursor ion and constant neutral loss scanning as a means of rapidly detecting drug metabolites is evaluated. Four clinically useful drugs, namely (i) cyclophosphamide, (ii) mifentidine, (iii) cimetropium bromide and (iv) haloperidol, were subjected to microsomal incubations to afford phase I metabolites. Aside from a minor clean-up procedure involving zinc sulfate precipitation of microsomal proteins and solid-phase extraction of metabolites using a Sep-pak C-18 cartridge, the mixtures were analysed directly by fast atom bombardment tandem mass spectrometry. It is demonstrated that such screening strategies are important in detecting novel metabolites. However, there are some problems associated with only using such methods, including (i) the possibility of not detecting metabolites that undergo unusual collision-induced dissociation fragmentation pathways, (ii) the non-detection of metabolites that have undergone metabolic change at unusual sites of reactivity, and (iii) production of artifacts derived from the parent drug by the primary ionization process. Examples are discussed that highlight both the strengths and weaknesses of such an approach.

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Rapid and efficient purification of cimetropium bromide and mifentidine drug metabolite mixtures derived from microsomal incubates for analysis by mass spectrometry

Cited by 20 publications

References 24 publications

In vitro studies on the metabolic fate of mifentidine, a novel histamine H2-receptor antagonist

In vitro studies on the metabolic fate of mifentidine, a novel histamine H2-receptor antagonist

A rapid and sensitive liquid chromatography/positive ion tandem mass spectrometry method for the determination of cimetropium in human plasma by liquid–liquid extraction

An evaluation of tandem mass spectrometry in drug metabolism studies

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