P450 Phenotyping of the Metabolism of Selegiline to Desmethylselegiline and Methamphetamine

Benetton, Salete; Fang, Carol; Yang, Yan-ou; Alok, Ramya; Year, Mey; Lin, Chin‐Chung; Yeh, Li‐Tain

doi:10.2133/dmpk.22.78

Cited by 28 publications

(17 citation statements)

References 12 publications

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“…This enhancement in inhibition was more dramatic in CYP2A6 compared with HLMs, which might reflect the metabolism of selegiline in HLMs by other CYPs such as CYP2B6 and CYP2C8 (Benetton et al, 2007), thus reducing its availability to inhibit CYP2A6. More importantly, the inhibition of CYP2A6, in addition to being competitive, was probably mechanismbased.…”

Section: Inhibition Of Nicotine Metabolism By Selegiline 997mentioning

confidence: 95%

“…Selegiline belongs to the acetylene group of compounds that contain a carboncarbon triple bond, which are known to be potent mechanismbased inhibitors (Correia and Ortiz de Montellano, 2005). Because the main human nicotine-metabolizing enzyme CYP2A6 seems to play a role in the metabolism of selegiline in vitro (Benetton et al, 2007), we examined whether selegiline and its metabolites (desmethylselegiline, L-methamphetamine, and L-amphetamine) (Shin, 1997) could inhibit nicotine metabolism in vitro in human and mouse hepatic microsomes, as well by both cDNA-expressed major human nicotine-metabolizing enzyme CYP2A6 and mouse CYP2A5 (Murphy et al, 2005;Siu and Tyndale, 2007). Genetically slow CYP2A6 metabolizers have a greater likelihood (1.75-fold) of quitting smoking (Gu et al, 2000), suggesting that if selegiline inhibits nicotine metabolism, this may be an additional mechanism through which it reduces smoking.…”

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confidence: 99%

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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: 95%

mentioning

confidence: 99%

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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“…Likewise, drug interactions with imipramine and selegiline have been described previously (Abernethy et al, 1984;Laine et al, 1999). The latter is a CYP2B6 and CYP2C19 substrate, also with a low oral bioavailability (Ͻ10%), and greater than 10-fold increases in AUC have been reported with OCs (Laine et al, 1999;Benetton et al, 2007). More importantly, the contribution of CYP2C19 after oral dosing of selegiline is thought to be minimal (Laine et al, 2001).…”

mentioning

confidence: 97%

Further Assessment of 17α-Ethinyl Estradiol as an Inhibitor of Different Human Cytochrome P450 Forms in Vitro

Chang¹,

Chen²,

Yang³

et al. 2009

Drug Metab Dispos

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ABSTRACT:17␣-Ethinyl estradiol (EE) was systematically evaluated as a reversible and time-dependent inhibitor of 11 human drug-metabolizing cytochromes P450 (P450s) (CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2J2, CYP3A4, and CYP3A5) in vitro. When ranked, the lowest IC 50 Reports continue to appear describing drug interactions involving oral contraceptive (OC) formulations containing 17␣-ethinyl estradiol (EE). For example, Hilli et al. (2008) reported recently that melatonin (MEL) area under the plasma concentration versus time curve (AUC) is increased (ϳ5-fold), and the 6-hydroxy melatonin (MEL 6-OH)/ MEL AUC ratio is decreased (88%). CYP1A2 is known to play a major role in the metabolism of MEL in human liver microsomes (HLM), so the authors deduced that the enzyme was the locus of the interaction (Facciolá et al., 2001;Härtter et al., 2001;Ma et al., 2005). EE-containing OCs exert a similar effect on the pharmacokinetics (PK) of tizanidine (Granfors et al., 2005). Both tizanidine and MEL are low oral bioavailability (Ͻ25%) CYP1A2 substrates because of first-pass metabolism (Härtter et al., 2001;Granfors et al., 2005). Although caffeine and theophylline also serve as CYP1A2 substrates, they undergo minimal first pass, are highly bioavailable, and the impact of EE is less marked (ϳ40% decrease in clearance) (Roberts et al., 1983;Balogh et al., 1995). Despite these clinical data, it is only very recently that assessment of CYP1A2 inhibition in vitro has been described previously (Karjalainen et al., 2008). In fact, Karjalainen et al. (2008) reported EE as a relatively weak inhibitor of phenacetin O-deethylation (POD) activity in HLM (low K m component; IC 50 ϭ 24 M).Drug interactions with EE-containing OC formulations have also included a number of CYP2C19 substrates, such as omeprazole, mephenytoin, and proguanil (Hägg et al., 2001; Rodrigues and Lu, 2004, references therein;Shelepova et al., 2005). Likewise, drug interactions with imipramine and selegiline have been described previously (Abernethy et al., 1984;Laine et al., 1999). The latter is a CYP2B6 and CYP2C19 substrate, also with a low oral bioavailability (Ͻ10%), and greater than 10-fold increases in AUC have been reported with OCs (Laine et al., 1999;Benetton et al., 2007). More importantly, the contribution of CYP2C19 after oral dosing of selegiline is thought to be minimal (Laine et al., 2001). Although CYP2B6 is implicated, there are no reports describing the impact of CYP2B6 genotype (or phenotype) on the oral PK of selegiline, and its contribution in vivo is not known. Moreover, the clinical drug interaction between EE and a CYP2B6 probe (bupropion) is not significant despite evidence for mechanism-based inhibition in vitro Palovaara et al., 2003). The same can also be said for the observed mechanism-based inhibition of CYP3A4 and CYP3A5 in vitro because the effect of EE on the PK of CYP3A substrates (e.g., midazolam and nifedipine) is minimal (Balogh et al., 1998; Article, publication date, and citation information c...

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“…Previous metabolism studies performed in vitro have shown that CYP2B6 and CYP2C19 are the major enzymes responsible for the metabolism of selegiline in human liver (Hidestrand et al, 2001;Benetton et al, 2007). The involvement of CYP3A4 and CYP1A2 in selegiline metabolism in humans has also been suggested by Taavitsainen et al (2000).…”

Section: Introductionmentioning

confidence: 91%

Inhibition of Bupropion Metabolism by Selegiline: Mechanism-Based Inactivation of Human CYP2B6 and Characterization of Glutathione and Peptide Adducts

2012

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ABSTRACT:Selegiline, the R-enantiomer of deprenyl, is used in the treatment of Parkinson's disease. Bupropion, an antidepressant, often used to treat patients in conjunction with selegiline, is metabolized primarily by CYP2B6. The effect of selegiline on the enzymatic activity of human cytochrome CYP2B6 in a reconstituted system and its effect on the metabolism of bupropion were examined. Selegiline was found to be a mechanism-based inactivator of the 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation (7-EFC) activity of CYP2B6 as well as bupropion metabolism. The inactivations were time-, concentration-, and NADPH-dependent and were characterized by K I values of 0.14 and 0.6 M, k inact values of 0.022 and 0.029 min ؊1, and t 1/2 values of 31.5 and 24 min, respectively. In standard inhibition assays, selegiline increased the K m of CYP2B6 for bupropion from 10 to 92 M and decreased the k cat by ϳ50%. The reduced carbon-monoxide difference spectrum revealed over a 50% loss in the cytochrome P450 spectrum in the inactivated sample, with no loss in heme, and there was ϳ70% loss in enzyme activity. Trapping of the reactive metabolite using GSH led to the identification of a GSH-selegiline conjugate with a m/z 528 that could be explained by hydroxylation of selegiline followed by the addition of glutathione to the propargyl moiety after oxygenation to form the ketene intermediate. Liquid chromatography-tandem mass spectrometry analysis of the labeled protein following digestion with trypsin revealed the peptide 64 DVFTVHLGPR 73 as the peptide modified by the reactive metabolite of selegiline and the site of adduct formation is Asp64.

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P450 Phenotyping of the Metabolism of Selegiline to Desmethylselegiline and Methamphetamine

Cited by 28 publications

References 12 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

Further Assessment of 17α-Ethinyl Estradiol as an Inhibitor of Different Human Cytochrome P450 Forms in Vitro

Inhibition of Bupropion Metabolism by Selegiline: Mechanism-Based Inactivation of Human CYP2B6 and Characterization of Glutathione and Peptide Adducts

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