Study of human urinary metabolism of fenfluramine using gas chromatography—mass spectrometry

Brownsill, R. D.; Wallace, D.; Taylor, A. R.; Campbell, Bruce

doi:10.1016/0378-4347(91)80584-y

Cited by 22 publications

(10 citation statements)

References 1 publication

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“…For instance, the addition of methylenedioxy and methyl groups to amphetamine, which leads to methylenedioxymetamphetamine (MDMA, Scheme 4) gives rise to a mass spectrum containing an abundant fragment at m/z 58 accounting for the above identified ethylidene methyl ammonium ion, while the fragment ion at m/z 91 is incremented by 46 mass units to m/z 135 (DeRuiter, Clark, & Noggle, 1990). The addition of an ethyl function to amphetamine in addition to a trifluoromethyl substitution of the phenyl residue yields fenfluoramine (Scheme 4), which generates a base peak at m/z 72 and a minor fragment at m/z 159 that correspond to m/z 44 and 91, respectively (Brownsill et al, 1991).…”

Section: Stimulantsmentioning

confidence: 99%

Mass spectrometry in sports drug testing: Structure characterization and analytical assays

Thevis

Schänzer

2006

Mass Spectrometry Reviews

176

128

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Owing to the sensitive, selective, and unambiguous nature of mass spectrometric analyses, chromatographic techniques interfaced to various kinds of mass spectrometers have become the most frequently employed strategy in the fight against doping. To obtain utmost confidence in analytical assays, mass spectrometric characterization of target analytes and typical dissociation pathways have been utilized as basis for the development of reliable and robust screening as well as confirmation procedures. Methods for qualitative and/or quantitative determinations of prohibited low and high molecular weight drugs have been established in doping control laboratories preferably employing gas or liquid chromatography combined with electron, chemical, or atmospheric pressure ionization followed by analyses using quadrupole, ion trap, linear ion trap, or hyphenated techniques. The versatility of modern mass spectrometers enable specific as well as comprehensive measurements allowing sports drug testing laboratories to determine the misuse of therapeutics such as anabolic-androgenic steroids, stimulants, masking agents or so-called designer drugs in athletes' blood or urine specimens, and a selection of recent developments is summarized in this review.

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Section: Stimulantsmentioning

confidence: 99%

Mass spectrometry in sports drug testing: Structure characterization and analytical assays

Thevis

Schänzer

2006

Mass Spectrometry Reviews

176

128

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“…All metabolites detected by MRS and radiolabeled studies are trifluorinated compounds. This is a reasonable assumption, because there is no evidence of metabolic loss of the trifluoromethyl moiety, and most of the DF administered to human subjects is excreted as DF, dNF, or one of three other trifluorinated metabolites (22).…”

Section: Correction For Drug Plus Metabolites In Nonbrain Tissuementioning

confidence: 99%

Quantitation of dexfenflurainine/d‐norfenfluramine concentration in primate brain using ¹⁹F NMR spectroscopy

Christensen¹,

Babb²,

Cohen³

et al. 1998

Magnetic Resonance in Med

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Fluorine (19F) magnetic resonance spectroscopy (MRS) was used to quantify the combined concentration of the anorectic drug dexfenfluramine (DF) and its active metabolite d-norfenfluramine (dNF) in rhesus monkey brain. The accuracy of the MRS technique was assessed by comparison with gas chromatography. Brain 19F MRS signals were converted to brain DF + dNF concentrations after correction for signal relaxation losses and drug distribution in nonbrain tissue. Gas chromatography (GC) was used to assay brain DF and dNF concentrations following MRS evaluation. DF + dNF concentrations measured by 19F MRS averaged 104 +/- 36 microM (mean +/- SD) and GC measurements averaged 71 +/- 12 microM. Correction for the distribution of DF and its metabolites in nonbrain tissue yielded a DF + metabolite brain concentration that was within one standard deviation of the GC-derived value. The concentration of DF plus dNF measured by 19F MRS was similar to or greater than the value obtained by GC, which indicates that DF and its active metabolite dNF are fully detected by 19F MRS in primate brain in vivo. The application of these techniques to human subjects should enable the measurement of low micromolar-range brain concentrations of DF and other fluorinated drugs.

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“…14 , 16 ASMs that are substrates of drug transporters are potential DDI victims. Earlier reports document FFA and nFFA metabolism, 9 , 12 , 17 , 18 but FFA metabolism has not been fully characterized in the context of predicting DDIs when used as an add‐on to existing ASM regimens in patients with DS or LGS. In vitro studies conducted according to DDI guidance have not yet been reported.…”

Section: Introductionmentioning

confidence: 99%

In vitro evaluation of fenfluramine and norfenfluramine as victims of drug interactions

Martin

Czerwiński

Limaye

et al. 2022

Pharmacology Res & Perspec

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Fenfluramine (FFA) has potent antiseizure activity in severe, pharmacoresistant childhood‐onset developmental and epileptic encephalopathies (e.g., Dravet syndrome). To assess risk of drug interaction affecting pharmacokinetics of FFA and its major metabolite, norfenfluramine (nFFA), we conducted in vitro metabolite characterization, reaction phenotyping, and drug transporter−mediated cellular uptake studies. FFA showed low in vitro clearance in human liver S9 fractions and in intestinal S9 fractions in all three species tested (t 1/2 > 120 min). Two metabolites (nFFA and an N‐oxide or a hydroxylamine) were detected in human liver microsomes versus six in dog and seven in rat liver microsomes; no metabolite was unique to humans. Selective CYP inhibitor studies showed FFA metabolism partially inhibited by quinidine (CYP2D6, 48%), phencyclidine (CYP2B6, 42%), and furafylline (CYP1A2, 32%) and, to a lesser extent (<15%), by tienilic acid (CYP2C9), esomeprazole (CYP2C19), and troleandomycin (CYP3A4/5). Incubation of nFFA with rCYP1A2, rCYP2B6, rCYP2C19, and rCYP2D6 resulted in 10%−20% metabolism and no clear inhibition of nFFA metabolism by any CYP‐selective inhibitor. Reaction phenotyping showed metabolism of FFA by recombinant human cytochrome P450 (rCYP) enzymes rCYP2B6 (10%–21% disappearance for 1 and 10 µM FFA, respectively), rCYP1A2 (22%−23%), rCYP2C19 (49%−50%), and rCYP2D6 (59%−97%). Neither FFA nor nFFA was a drug transporter substrate. Results show FFA metabolism to nFFA occurs through multiple pathways of elimination. FFA dose adjustments may be needed when administered with strong inhibitors or inducers of multiple enzymes involved in FFA metabolism (e.g., stiripentol).

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Study of human urinary metabolism of fenfluramine using gas chromatography—mass spectrometry

Cited by 22 publications

References 1 publication

Mass spectrometry in sports drug testing: Structure characterization and analytical assays

Mass spectrometry in sports drug testing: Structure characterization and analytical assays

Quantitation of dexfenflurainine/d‐norfenfluramine concentration in primate brain using ¹⁹F NMR spectroscopy

In vitro evaluation of fenfluramine and norfenfluramine as victims of drug interactions

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Study of human urinary metabolism of fenfluramine using gas chromatography—mass spectrometry

Cited by 22 publications

References 1 publication

Mass spectrometry in sports drug testing: Structure characterization and analytical assays

Mass spectrometry in sports drug testing: Structure characterization and analytical assays

Quantitation of dexfenflurainine/d‐norfenfluramine concentration in primate brain using 19F NMR spectroscopy

In vitro evaluation of fenfluramine and norfenfluramine as victims of drug interactions

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Quantitation of dexfenflurainine/d‐norfenfluramine concentration in primate brain using ¹⁹F NMR spectroscopy