Studies on the metabolism and the toxicological analysis of the nootropic drug fipexide in rat urine using gas chromatography–mass spectrometry

Staack, Roland F.; Maurer, Hans H.

doi:10.1016/j.jchromb.2004.01.035

Cited by 17 publications

(13 citation statements)

References 28 publications

(40 reference statements)

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“…4) are consistent with this assignment. This compound has also been detected previously as an in vivo metabolite of fipexide in rat 11. An overview of the in vitro phase I metabolism of fipexide is shown in Fig.…”

Section: Resultssupporting

confidence: 65%

“…The species at m/z 229, found only in rat liver microsomal incubations, was tentatively identified as N ‐[2‐(4‐chlorophenoxyacetyl)ethylenediamine (4‐CP‐acetylethylenediamine), formed via N‐didealkylation of fipexide. This compound has previously been detected by gas chromatography (GC)/MS analysis of rat urine following fipexide dosing 11. Its MS/MS spectrum is illustrated in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This binding is considered to play a major role in drug toxicity. Fipexide is extensively metabolized by hydrolysis to form 1‐(3,4‐methylenedioxy)benzylpiperazine (MDBP) and 4‐chlorophenoxyacetic acid (4‐CPA) 11. MDBP belongs to the class of piperazine designer drugs and is structurally similar to the methylenedioxy‐substituted amphetamine derivatives, 3,4‐methylenedioxymetamphetamine (MDMA, Ecstasy) and 3,4‐methylenedioxyamphetamine (MDA).…”

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confidence: 99%

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Investigating the in vitro metabolism of fipexide: characterization of reactive metabolites using liquid chromatography/mass spectrometry

Sleno

Staack

Varesio

et al. 2007

Rapid Comm Mass Spectrometry

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The in vitro metabolism of the nootropic drug fipexide was studied using different liquid chromatography/mass spectrometry (LC/MS) techniques. This drug has been withdrawn from the market due to toxic effects. No previous reports have investigated the possible involvement of reactive metabolites in the toxicity of fipexide. The hydrolysis of this drug leads to the formation of two potentially toxic species, 3,4-methylenedioxybenzylpiperazine (MDBP) and 4-chlorophenoxyacetic acid (4-CPA). Here, we investigate the in vitro metabolism of fipexide in human, rat, mouse and dog, as well as of MDBP and 4-CPA in human and rat, while focusing on the formation of reactive metabolites. A combination of LC/MS analyses on a hybrid quadrupole-linear ion trap instrument and accurate mass data from QqTOF measurements was employed for the characterization of these metabolites. Microsomal metabolites of fipexide were MDBP, 4-CPA, fipexide N-oxide or hydroxyl, demethylenated fipexide and other minor ones, all of which were investigated by tandem mass spectrometry. Reactive metabolites were detected using several trapping procedures with small molecules such as glutathione, its ethyl ester derivative and N-acetylcysteine. The demethylenated metabolite, a catechol, formed its corresponding ortho-quinone, which readily reacts with these nucleophiles. MDBP was studied in a similar manner, due to its ability to form an analogous catechol. Because of its acidic nature, 4-CPA was assessed for possible acylglucuronide and acyl-CoA thioester metabolites, which could also be involved in bioactivation pathways. Several important metabolites were identified as potential mediators of toxicity via protein binding.

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Section: Resultssupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Investigating the in vitro metabolism of fipexide: characterization of reactive metabolites using liquid chromatography/mass spectrometry

Sleno

Staack

Varesio

et al. 2007

Rapid Comm Mass Spectrometry

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“…However, unambiguous assignment of these isomers to a certain peak was not possible owing to the similarity of the mass spectra, which is why the isomers are referred to as isomer 1 and isomer 2. In case of 3 0 -hydroxylation, two peaks with practically identical mass spectra were observed only for part of the metabolites, namely N-dealkyl-3 0 -hydroxy PCEPA (18,19) and dehydrated 3 0 -hydroxy-carboxy PCEPA (24,25). For the same reason as mentioned above, unambiguous stereochemical assignment was not possible, and the compounds were again referred to as isomer 1 and isomer 2.…”

Section: Bond In Positionmentioning

confidence: 94%

“…0 -hydroxy PCEPA (20), dehydrated carboxy PCEPA (21), dehydrated carboxy-4 0 -hydroxy PCEPA isomer 1 (22), dehydrated carboxy-4 0 -hydroxy-PCEPA isomer 2 (23), dehydrated carboxy-3 0 -hydroxy-PCEPA isomer 1 (24), and dehydrated carboxy-3 0 -hydroxy-PCEPA isomer 2 (25). In the trimethylsilylated urine extract, PCEPA and the trimethylsilyl derivatives of the following compounds could be additionally identified: carboxy PCEPA (26), carboxy-hydroxyphenyl PCEPA (27), cis-carboxy-4 0 -hydroxy PCEPA (28), transcarboxy-4 0 -hydroxy PCEPA (29), carboxy-3 0 -hydroxy PCEPA Figure 1.…”

Section: Identification Of the Metabolitesmentioning

confidence: 99%

New designer drug N‐(1‐phenylcyclohexyl)‐3‐ethoxypropanamine (PCEPA): Studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques

et al. 2006

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Studies are described on the metabolism and toxicological detection of the phencyclidine-derived designer drug N-(1-phenylcyclohexyl)-3-ethoxypropanamine (PCEPA) in rat urine using gas chromatographic/mass spectrometric techniques. The identified metabolites indicated that PCEPA was metabolized by N-dealkylation, O-deethylation partially followed by oxidation of the resulting alcohol to the corresponding carboxylic acid, hydroxylation of the cyclohexyl ring at different positions of PCEPA, N-dealkyl PCEPA, O-deethyl PCEPA, and of the corresponding carboxylic acids. Finally, aromatic hydroxylation of PCEPA, the corresponding carboxylic acids, and O-deethyl PCEPA, the latter partially followed by oxidation to the corresponding carboxylic acid and hydroxylation of the cyclohexyl ring could be observed. All metabolites were partially excreted in the conjugated form. The authors' systematic toxicological analysis (STA) procedure using full-scan GC/MS after acid hydrolysis, liquid-liquid extraction, and microwave-assisted acetylation allowed the detection in rat urine of an intake of a common drug users' dose of PCEPA. Assuming a similar metabolism in humans, the STA in human urine should be suitable as proof of intake of PCEPA.

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Pitfalls in drug testing by hyphenated low‐ and high‐resolution mass spectrometry

Maurer

2020

Drug Testing and Analysis

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This paper reviews various pitfalls observed during developing, validation, application, and interpretation of drug testing approaches using GC-MS and low-and high-resolution LC-MS. They include sampling and storage of body samples, sample adulteration and contamination, analyte stability, sample preparation without or with cleavage of conjugates, extraction, derivatization, internal standardization, false negative and positive results by GC-MS or LC-MS screening and/or confirmation procedures including artifact formation, ion suppression or enhancement by electrospray ionization, and finally pitfalls in data interpretation. Conclusions and prospects close the Tutorial. K E Y W O R D S

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Studies on the metabolism and the toxicological analysis of the nootropic drug fipexide in rat urine using gas chromatography–mass spectrometry

Cited by 17 publications

References 28 publications

Investigating the in vitro metabolism of fipexide: characterization of reactive metabolites using liquid chromatography/mass spectrometry

Investigating the in vitro metabolism of fipexide: characterization of reactive metabolites using liquid chromatography/mass spectrometry

New designer drug N‐(1‐phenylcyclohexyl)‐3‐ethoxypropanamine (PCEPA): Studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques

Pitfalls in drug testing by hyphenated low‐ and high‐resolution mass spectrometry

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