Novel substrates and products of amine oxidase-catalysed reactions

Youdin, M. B. H.; Harshak, N.; Yoshioka, Masato; Araki, Hiroshi; Mukai, Yu; Gotto, G.

doi:10.1042/bst0190224

Cited by 15 publications

(8 citation statements)

References 3 publications

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“…Similar to sumatriptan and zolmitriptan [2–4], the primary route of metabolism of rizatriptan is via monoamine oxidase‐A (MAO‐A) to the indole‐acetic acid derivative. MAO is reportedly capable of catalysing the oxidative deamination of primary, secondary and tertiary amines [5]. Oxidative metabolism via cytochrome P450 appears to be a minor route of metabolism of this compound.…”

Section: Introductionmentioning

confidence: 99%

The effects of moclobemide on the pharmacokinetics of the 5‐HT_1B/1D agonist rizatriptan in healthy volunteers

Haarst

Gerven

Cohen

et al. 1999

Brit J Clinical Pharma

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AimsThe new 5-HT 1B/1D agonist rizatriptan (MK-0462) has recently been registered for the treatment of migraine. Its primary route of metabolism is via monoamine oxidase-A (MAO-A). Antidepressants such as the MAO-A inhibitor moclobemide may be used in patients with chronic headache syndromes. Hence, this study aimed to investigate the interactions between rizatriptan and moclobemide. Methods In a double-blind, randomized, placebo-controlled, two-period cross-over study 12 healthy, young volunteers (six males, six females) were treated with moclobemide (150 mg twice daily) or placebo for 4 days. On the fourth day, a single dose of rizatriptan (10 mg) was administered, and subsequently blood and urine samples were collected for assay of rizatripan and N-monodesmethyl rizatriptan. Plasma concentrates of 3,4-dihydroxyphenylglycol (DHPG), a marker of MAO-A inhibition, were also assessed. Supine and standing blood pressure were measured regularly. Results Both treatments were well tolerated. During moclobemide, the increase in supine diastolic blood pressure following rizatriptan administration was augmented. Inhibition of MAO by moclobemide was inferred from a persistent decrease in DHPG level (43% on average). When rizatriptan was coadministered with moclobemide, the area under the plasma drug concentration-time profiles for rizatriptan and its N-monodesmethyl metabolite increased 2.2-fold (90% CI, 1.93-2.47) and 5.3-fold (90% CI, 4.81-5.91), respectively, when compared with placebo. Peak plasma drug concentrations for rizatriptan and its n-monodesmethyl metabolite increased 1.4-fold (90% CI, 1.11-1.80) and 2.6-fold (90% CI, 2.23-3.14), respectively, and half-lives of both were prolonged. Conclusions Moclobemide inhibited the metabolism of rizatriptan and its active Nmonodesmethyl metabolite through inhibition of MAO-A. Thus, moclobemide may considerably potentiate rizatriptan action. Concurrent administration of moclobemide and rizatriptan is not recommended.

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Section: Introductionmentioning

confidence: 99%

The effects of moclobemide on the pharmacokinetics of the 5‐HT_1B/1D agonist rizatriptan in healthy volunteers

Haarst

Gerven

Cohen

et al. 1999

Brit J Clinical Pharma

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“…N-acetyl polyamines have been reported to be good substrates for MAO-B (Youdim et al, 1991;Bentué-Ferrer et al, 1996), although the compounds are thought to normally be metabolised by polyamine oxidase in vivo (Pegg, 1986;Seiler, 1987). This affinity of N-acetyl polyamines for MAO-B, coupled with the correlation of SSAT induction and cell death, suggested that an investigation of the effects of N-acetyl polyamines on apoptotic pathways was warranted.…”

Section: Introductionmentioning

confidence: 99%

N8-acetyl spermidine protects rat cerebellar granule cells from low K+-induced apoptosis

Berry

1999

J. Neurosci. Res.

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The endogenous polyamines have been extensively studied with respect to their role in cellular death mechanisms, although the results are contradictory. In contrast, their primary metabolites, the N-acetyl polyamines, have not been much studied. It has been hypothesized that the N-acetyl metabolites may play a role in cellular death mechanisms, and some of the variability between different reports may be due to altered polyamine metabolic capacities. Using primary cultures of rat cerebellar granule cells, the effects of N-acetyl metabolites have been examined on basal, cytosine beta-D-arabinofuranoside (Ara-C)-induced and low K+-induced apoptosis. None of the compounds affected either basal or Ara-C-induced apoptosis at low doses. At higher doses, all compounds were toxic. Two compounds, N8-acetyl spermidine and N1-acetyl spermine, were found to protect cells from low K+-induced apoptosis, which has been shown to be p53-independent. In contrast, the parent polyamines were devoid of protective activity at subtoxic doses. This represents the first time that an antiapoptotic effect of N-acetyl polyamines has been demonstrated. These results raise the possibility that these compounds may act as endogenous neuroprotectants. The lack of effect on basal apoptosis provides evidence of at least two forms of p53-independent apoptosis that can be regulated independently.

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“…Back conversion of spermine to spermidine, and spermidine to putrescine can occur after N 1 -acetylation by spermidine/spermine N 1 -acetyltransferase, and subsequent oxidation by polyamine oxidase (EC 1.5.3.11). A distinct spermine/ spermidine N 8 -acetylation pathway is also present, which may generate substrates of MAO (Youdim et al, 1991). Cadaverine is produced by direct decarboxylation of lysine through the action of lysine decarboxylase (EC 4.1.1.18; Table 1).…”

Section: F Polyaminesmentioning

confidence: 99%

Trace Amines and Their Receptors

Gainetdinov¹,

Hoener²,

Berry³

2018

Pharmacol Rev

276

287

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Novel substrates and products of amine oxidase-catalysed reactions

Cited by 15 publications

References 3 publications

The effects of moclobemide on the pharmacokinetics of the 5‐HT_1B/1D agonist rizatriptan in healthy volunteers

The effects of moclobemide on the pharmacokinetics of the 5‐HT_1B/1D agonist rizatriptan in healthy volunteers

N8-acetyl spermidine protects rat cerebellar granule cells from low K+-induced apoptosis

Trace Amines and Their Receptors

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Novel substrates and products of amine oxidase-catalysed reactions

Cited by 15 publications

References 3 publications

The effects of moclobemide on the pharmacokinetics of the 5‐HT1B/1D agonist rizatriptan in healthy volunteers

The effects of moclobemide on the pharmacokinetics of the 5‐HT1B/1D agonist rizatriptan in healthy volunteers

N8-acetyl spermidine protects rat cerebellar granule cells from low K+-induced apoptosis

Trace Amines and Their Receptors

Contact Info

Product

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The effects of moclobemide on the pharmacokinetics of the 5‐HT_1B/1D agonist rizatriptan in healthy volunteers

The effects of moclobemide on the pharmacokinetics of the 5‐HT_1B/1D agonist rizatriptan in healthy volunteers