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

Lévai, F; Fejer, E.; Szeleczky, Gábor; Szabó, Anna; Erős-Takácsy, Tünde; Hajdu, F.; Szebeni, G; Szatmári, István; Hermecz, I.

doi:10.1007/bf03190594

Cited by 9 publications

(5 citation statements)

References 24 publications

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“…None of the tested selegiline metabolites inhibited CYP2A5 with greater potency compared with selegiline. However, another metabolite that is produced in mice is selegiline-N-oxide (Lévai et al, 2004). It is possible that in addition to the compounds tested here that selegiline-N-oxide, produced by other enzymes in MLMs, can also inhibit CYP2A5-mediated nicotine metabolism.…”

Section: Inhibition Of Nicotine Metabolism By Selegiline 997mentioning

confidence: 93%

Selegiline Is a Mechanism-Based Inactivator of CYP2A6 Inhibiting Nicotine Metabolism in Humans and Mice

Siu¹,

Tyndale²

2007

J Pharmacol Exp Ther

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Selegiline (L-deprenyl) is in clinical treatment trials as a potential smoking cessation drug. We investigated the affect of selegiline and its metabolites on nicotine metabolism. In mice, selegiline was a potent inhibitor of nicotine metabolism in hepatic microsomes and cDNA-expressed CYP2A5; the selegiline metabolites desmethylselegiline, L-methamphetamine, and L-amphetamine, also inhibited nicotine metabolism. Pretreatment with selegiline and desmethylselegiline increased inhibition (IC 50 ) in microsomes by 3.3-and 6.1-fold, respectively. In mice in vivo, selegiline increased AUC (90.7 Ϯ 5.8 versus 57.4 Ϯ 5.3 ng/h/ml, p Ͻ 0.05), decreased clearance (4.6 Ϯ 0.4 versus 7.3 Ϯ 0.3 ml/min, p Ͻ 0.05), and increased elimination half-life (12.5 Ϯ 6.3 versus 6.6 Ϯ 1.4 min, p Ͻ 0.05) of nicotine. In vitro, selegiline was a potent inhibitor of human nicotine metabolism in hepatic microsomes and cDNA-expressed CYP2A6; desmethylselegiline and L-amphetamine also inhibited nicotine metabolism. Selegiline preincubation increased inhibition in microsomes (3.7-fold) and CYP2A6 (14.8-fold); the K i for CYP2A6 was 4.2 M. Selegiline dose-and time-dependently inhibited nicotine metabolism by CYP2A6 (K I ϭ 15.6 Ϯ 2.7 M; k inact ϭ 0.34 Ϯ 0.04 min Ϫ1 ), and the inhibition was irreversible in the presence of NADPH, indicating that it is a mechanism-based inhibitor of CYP2A6. Thus, inhibition of mouse nicotine metabolism by selegiline was competitive in vitro and significantly increased plasma nicotine in vivo. In humans, where selegiline is both a competitive and mechanismbased inhibitor, it is likely to have even greater effects on in vivo nicotine metabolism. Our findings suggest that an additional potential mechanism of selegiline in smoking cessation is through inhibition of nicotine metabolism.

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Section: Inhibition Of Nicotine Metabolism By Selegiline 997mentioning

confidence: 93%

Selegiline Is a Mechanism-Based Inactivator of CYP2A6 Inhibiting Nicotine Metabolism in Humans and Mice

Siu¹,

Tyndale²

2007

J Pharmacol Exp Ther

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“…This detected but unidentified metabolite could be deprenyl-N-oxide (DNO). Recently, in vivo formation of N-oxide metabolite from R-deprenyl in humans was shown by HPLC and HPLC-MS methods [35,36] and its in vitro production by liver microsomal preparations [42,102] was also demonstrated. The known metabolic pathways of selegiline are shown in Fig.…”

Section: Metabolism and Excretion Of R-deprenylmentioning

confidence: 97%

R-Deprenyl: Pharmacological Spectrum of its Activity

et al. 2010

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Deprenyl has been discovered by Knoll and co-workers. The R-enantiomer of deprenyl (selegiline) is a selective and irreversible inhibitor of the B-isoform of monoamine oxidase (MAO-B) enzyme. Due to its dopamine potentiating and possible neuroprotective properties it has an established role in the treatment of parkinsonian patients. By inhibiting MAO-B enzyme, R-deprenyl decreases the formation of hydrogen peroxide, alleviating the oxidative stress also reduced by increased expression of antioxidant enzymes (superoxide dismutases and catalase) reported during chronic treatment. It was shown to prevent the detrimental effects of neurotoxins like MPTP and DSP-4. R-Deprenyl elicits neuroprotective and neuronal rescue activities in concentrations too low to inhibit MAO-B. It is extensively metabolized and some of the metabolites possess pharmacological activities, thus their contribution to neuroprotective properties was also suggested. The recently identified deprenyl-N-oxide is extensively studied in our laboratory. Effects other than neuroprotection, like influencing cell adhesion and proliferation cannot be neglected.

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“…Both CYP3A4 and CYP2B6 are involved in two major oxidative pathways, whereas CYP1A2 participates in the formation of desmethylselegiline only. 21 CYP2B6 showed higher affinity for the metabolism of selegiline than CYP1A2 and CYP3A4 in humans. 22 However, the amount and activity of CYP450 in different species should be taken into consideration.…”

Section: Resultsmentioning

confidence: 87%

“…ginseng extracts on CYP450 in rats and humans in a previously published paper. , Cytochrome P450 enzymes, including CYP1A2, CYP3A4, and CYP2B6, participate in the metabolism of selegiline, which forms desmethyl-selegiline and l -methamphetamine. Both CYP3A4 and CYP2B6 are involved in two major oxidative pathways, whereas CYP1A2 participates in the formation of desmethyl-selegiline only . CYP2B6 showed higher affinity for the metabolism of selegiline than CYP1A2 and CYP3A4 in humans .…”

Section: Resultsmentioning

confidence: 95%

Preclinical Herb–Drug Pharmacokinetic Interaction of Panax ginseng Extract and Selegiline in Freely Moving Rats

Yang¹,

Li²,

Tsai

2020

ACS Omega

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Selegiline, an inhibitor of monoamine oxidase B, is prescribed during the early stages of Parkinson's disease. The nutritional herbal medicine Panax ginseng C.A. Meyer has been reported to show potential neuroprotective activity; however, the herb−drug pharmacokinetic interaction between selegiline and P. ginseng extract has not been characterized. Our hypothesis is that the ginseng extract and selegiline produce pharmacokinetic interactions at certain doses. To investigate this hypothesis, a validated ultraperformance liquid chromatography−tandem mass spectrometry (UPLC−MS/MS) method was developed to monitor selegiline in rat plasma. Experimental rats were divided into groups treated with selegiline alone (10 mg/kg, i.v.; 30 mg/kg, p.o.), with the low-dose ginseng extract (1 g/kg, p.o., for 5 consecutive days) or with the high-dose ginseng extract (3 g/kg, p.o., for 5 consecutive days). The pharmacokinetic results demonstrated that the oral bioavailability of selegiline alone was approximately 18%; however, when rats were pretreated with low and high doses of the ginseng extract, the bioavailability of selegiline was 7.2 and 29%, respectively. These results suggested that the ginseng extract may produce a biphasic pharmacokinetic phenomenon. In summary, ginseng alters the oral bioavailability of selegiline, and these observations might provide preclinical information concerning the pharmacokinetic interactions between selegiline and herbal supplements.

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

Cited by 9 publications

References 24 publications

Selegiline Is a Mechanism-Based Inactivator of CYP2A6 Inhibiting Nicotine Metabolism in Humans and Mice

Selegiline Is a Mechanism-Based Inactivator of CYP2A6 Inhibiting Nicotine Metabolism in Humans and Mice

R-Deprenyl: Pharmacological Spectrum of its Activity

Preclinical Herb–Drug Pharmacokinetic Interaction of Panax ginseng Extract and Selegiline in Freely Moving Rats

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