Urinary excretion of selegiline N -oxide, a new indicator for selegiline administration in man

Katagi, Munehiro; Tatsuno, Michiaki; Tsutsumi, Hiroe; Miki, Akihiro; Kamata, Tohru; Nishioka, Hiroshi; Nakajima, Kunio; Nishikawa, Mayumi; Tsuchihashi, Hitoshi

doi:10.1080/00498250210144857

Cited by 25 publications

(26 citation statements)

References 15 publications

(19 reference statements)

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“…Especially, because N-oxide metabolites readily degrade, as mentioned above, it is well known that N-oxides are normally undetectable by GC/MS. Thus, we concluded that the detection of "NЈ-oxide" (it should be named "hydroxylamine," rather than "NЈ-oxide") in their reports required reexamination by LC/MS, based on our previous studies that dealt with N-oxide metabolites of several other drugs (Katagi et al, 2000(Katagi et al, , 2001.…”

Section: Discussionmentioning

confidence: 99%

METABOLISM OF THE PSYCHOTOMIMETIC TRYPTAMINE DERIVATIVE 5-METHOXY-N,N-DIISOPROPYLTRYPTAMINE IN HUMANS: IDENTIFICATION AND QUANTIFICATION OF ITS URINARY METABOLITES

Kamata¹,

Katagi²,

Kamata³

et al. 2005

Drug Metab Dispos

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ABSTRACT:The urinary metabolites of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) in humans have been investigated by analyzing urine specimens from its users. For the unequivocal identification and accurate quantification of its major metabolites, careful analyses were conducted by gas chromatography/mass spectrometry, liquid chromatography/mass spectrometry, and liquid chromatography-tandem mass spectrometry, using authentic standards of each metabolite synthesized. Three major metabolic pathways were revealed as follows: 1) side chain degradation by O-demethylation to form 5-hydroxy-N,N-diisopropyltryptamine (5-OH-DIPT), which would be partly conjugated to its sulfate and glucuronide; 2) direct hydroxylation on position 6 of the aromatic ring of 5-MeO-DIPT, and/or methylation of the hydroxyl group on position 5 after hydroxylation on position 6 of the aromatic ring of 5-OH-DIPT, to produce 6-hydroxy-5-methoxy-N,N-diisopropyltryptamine (6-OH-5-MeO-DIPT), followed by conjugation to its sulfate and glucuronide; and 3) side chain degradation by N-deisopropylation, to the corresponding secondary amine 5-methoxy-N-isopropyltryptamine (5-MeO-NIPT). Of these metabolites, which retain structural characteristics of the parent drug, 5-OH-DIPT and 6-OH-5-MeO-DIPT were found to be more abundant than 5-MeO-NIPT. Although the parent drug 5-MeO-DIPT was detectable even 35 h after dosing, no trace of its N-oxide was detected in any of the specimens examined.

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Section: Discussionmentioning

confidence: 99%

METABOLISM OF THE PSYCHOTOMIMETIC TRYPTAMINE DERIVATIVE 5-METHOXY-N,N-DIISOPROPYLTRYPTAMINE IN HUMANS: IDENTIFICATION AND QUANTIFICATION OF ITS URINARY METABOLITES

Kamata¹,

Katagi²,

Kamata³

et al. 2005

Drug Metab Dispos

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“…Recently, the generation of another metabolite, deprenyl-N-oxide by flavincontaining monooxygenase (FMO) was proposed by Wu et al [26]. This compound was later identified in vitro in microsomal preparation (from F. Lévai et al, submitted) and in vivo in human urine [27,28]. The metabolic pathways of R-(2)-deprenyl are shown in Fig.…”

Section: Introductionmentioning

confidence: 94%

Chiral characterization of deprenyl‐N‐oxide and other deprenyl metabolites by capillary electrophoresis using a dual cyclodextrin system in rat urine

2003

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A chiral capillary electrophoresis method has been developed for the simultaneous separation of the enantiomers of deprenyl and eight of its metabolites, among them the recently described metabolite deprenyl-N-oxide. Although heptakis-(2,6-di-O-methyl)-beta-cyclodextrin (DIMEB) was suitable for the enantioresolution of deprenyl and its dealkylated derivatives, the enantiomers of deprenyl-N-oxide were just partly resolved. Carboxymethyl-beta-cyclodextrin (CMBCD) in as low as 2 mM concentration was capable of the enantiomer separation of all the nine examined compounds, however co-migration of 1R,2S-(-)-norephedrine and 1R,2R-(-)-pseudoephedrine, as well as 1S,2R-(+)-ephedrine and R-(-)-amphetamine was observed. This problem could be overcome by the use of a dual cyclodextrin system containing 4 mM DIMEB in addition to 2 mM CMBCD; simultaneous separation of all the compounds could be achieved. The optimized method was used for the analysis of rat urine samples after 10 days of treatment of animals with either R-(-)- or S-(+)-deprenyl. The stereospecific biotransformation of both deprenyl enantiomers was confirmed, and the stereoselectivity of N-oxide formation was demonstrated.

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“…Less selegiline-NOs were 106.85 4 : Formation of selegiline-N-oxide in rat microsomal preparation in vitro in the presence of specific isoenzyme inhibitors metabolites, numerous minor metabolites, such as phydroxydesmethylselegiline, p-hydroxymethamphetamine, p-hydroxyamphetamine, ephedrine, norephedrine, pseudoephedrine, norpseudoephedrine and phenylacetone have been identified in man and/or in various animal species (17). The formation of selegiline-NO as a metabolite of selegiline has previously been postulated (25,34) and it was recently identified in human urine (35,36).…”

Section: Resultsmentioning

confidence: 99%

In vitro formation of selegiline-N-oxide as a metabolite of selegiline in human, hamster, mouse, rat, guinea-pig, rabbit and dog

Lévai¹,

Fejer²,

Szeleczky³

et al. 2004

European Journal of Drug Metabolism and Pharmacokinetics

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It is well established in the litrature, that selegiline is metabolised to its N-dealkylated metabolites, N-desmethylselegiline, methamphetamine and amphetamine. However, most studies on selegiline metabolism did not characterize the species differences in the formation of the metabolites. Therefore, in this study, we investigated the in vitro metabolism of selegiline in liver microsomes of different species. In addition, to the previously well-characterized metabolites, selegiline-N-oxide (selegiline-NO) was found to be formed as a metabolite of selegiline in rat liver microsomal preparation. The results of experiments with liver microsomes from other species indicated species differences in the rate and extent of formation of selegiline-NO. The dog and hamster liver microsomal preparations were the most active in terms of selegiline-NO production, whereas little selegiline was metabolized to its N-oxide in human liver microsomes. When selegiline-NO was incubated with rat liver microsomes, no metabolism occurred. When a short incubation time was applied in selegiline expriments no increase in the amount of selegiline-NO was detected. Accordingly, it was clear that selegiline was not metabolized to the N-dealkylated or N,N-bis-dealkylated compounds via selegiline-NO. Studies with different isoenzyme inhibitors indicated that the formation of selegiline-NO might be catalyzed at least partly by cytochrome P450 (CYP) 2D6 and CYP3A4. With the exception of hamster microsomes in the microsomal preparations in vitro, the formation of the R,S-stereoisomer of selegiline-NO was preferred.

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Urinary excretion of selegiline N -oxide, a new indicator for selegiline administration in man

Cited by 25 publications

References 15 publications

METABOLISM OF THE PSYCHOTOMIMETIC TRYPTAMINE DERIVATIVE 5-METHOXY-N,N-DIISOPROPYLTRYPTAMINE IN HUMANS: IDENTIFICATION AND QUANTIFICATION OF ITS URINARY METABOLITES

METABOLISM OF THE PSYCHOTOMIMETIC TRYPTAMINE DERIVATIVE 5-METHOXY-N,N-DIISOPROPYLTRYPTAMINE IN HUMANS: IDENTIFICATION AND QUANTIFICATION OF ITS URINARY METABOLITES

Chiral characterization of deprenyl‐N‐oxide and other deprenyl metabolites by capillary electrophoresis using a dual cyclodextrin system in rat urine

In vitro formation of selegiline-N-oxide as a metabolite of selegiline in human, hamster, mouse, rat, guinea-pig, rabbit and dog

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