Detection and quantitation of a ring-hydroxylated metabolite of the antidepressant drug tranylcypromine

Baker, Glen B.; Hampson, David R.; Coutts, Ronald T.; Micetich, Ronald G.; Hall, T. W.; Rao, Tadimeti S.

doi:10.1007/bf01249085

Cited by 25 publications

(2 citation statements)

References 13 publications

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“…Because TCP undergoes ring hydroxylation, it is also presumably prone to metabolic interactions with other drugs which undergo similar metabolism and/or are inhibitors of hydroxylating enzymes. In an earlier study by Baker et al [1986], pretreatment of rats with iprindole, a compound that blocks ring hydroxylation of amphetamine, or with trifluperazine, a phenothiazine antipsychotic known to block CYP2D6, resulted in marked increases of TCP brain levels compared to values in vehicle-pretreated rats. However, in the present study pretreatment with iprindole or trifluperazine had no effect on brain levels of FTCP 2 h later when com- pared with values in rats pretreated with saline, indicating that this analog may be less susceptible than TCP to metabolic drug-drug interactions with inhibitors of CYP enzymes.…”

Section: Resultsmentioning

confidence: 95%

4-fluorotranylcypromine, a novel monoamine oxidase inhibitor: Neurochemical effects in rat brain after short- and long-term administration

Sherry¹,

Coutts²,

Baker³

1999

Drug Dev. Res.

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A series of acute and chronic experiments was conducted on 4‐fluorotranylcypromine (FTCP), an analog of the monoamine oxidase (MAO)‐inhibiting antidepressant tranylcypromine (TCP) in which the 4 position of the phenyl ring is protected from metabolism. These studies demonstrated that FTCP is a more potent inhibitor of MAO ex vivo than is the parent drug. Despite its similarity in structure to p‐chloroamphetamine, FTCP does not cause a depletion of brain levels of 5‐hydroxytryptamine (5‐HT) after chronic administration; in fact, it increases brain 5‐HT to levels similar to those produced by TCP. After chronic administration, FTCP produces a downregulation of β‐adrenergic and tryptamine receptors, in common with TCP and several other antidepressants. Pretreatment of rats with iprindole or trifluperazine, drugs known to block cytochrome P450‐mediated hydroxylation reactions and to elevate brain levels of TCP, had no effects on FTCP brain levels, suggesting that metabolic drug–drug interactions may be less of a concern with FTCP than with TCP. In vitro uptake experiments in prisms prepared from hypothalamus or striatum revealed that TCP and FTCP are both potent inhibitors of norepinephrine (NE) uptake; FTCP is a more potent inhibitor of 5‐HT uptake than is TCP. FTCP is a more potent releaser of 5‐HT than is TCP. Drug Dev. Res. 48:61–69, 1999. © 1999 Wiley‐Liss, Inc.

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Section: Resultsmentioning

confidence: 95%

4-fluorotranylcypromine, a novel monoamine oxidase inhibitor: Neurochemical effects in rat brain after short- and long-term administration

Sherry¹,

Coutts²,

Baker³

1999

Drug Dev. Res.

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show abstract

“…4. In an earlier study by Baker et al [1986], pretreatment of rats with iprindole, a compound that blocks ring hydroxylation of amphetamine, or with trifluperazine, a phenothiazine antipsychotic known to block CYP2D6, resulted in marked increases of TCP brain levels compared to values in vehicle-pretreated rats. Results are expressed as percent inhibition of control (vehicle-treated) MAO-A activity (n = 4-8).…”

Section: Resultsmentioning

confidence: 95%

4‐fluorotranylcypromine, a novel monoamine oxidase inhibitor: Neurochemical effects in rat brain after short‐ and long‐term administration

1999

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A series of acute and chronic experiments was conducted on 4-fluorotranylcypromine (FTCP), an analog of the monoamine oxidase (MAO)-inhibiting antidepressant tranylcypromine (TCP) in which the 4 position of the phenyl ring is protected from metabolism. These studies demonstrated that FTCP is a more potent inhibitor of MAO ex vivo than is the parent drug. Despite its similarity in structure to pchloroamphetamine, FTCP does not cause a depletion of brain levels of 5-hydroxytryptamine (5-HT) after chronic administration; in fact, it increases brain 5-HT to levels similar to those produced by TCP. After chronic administration, FTCP produces a downregulation of β-adrenergic and tryptamine receptors, in common with TCP and several other antidepressants. Pretreatment of rats with iprindole or trifluperazine, drugs known to block cytochrome P450-mediated hydroxylation reactions and to elevate brain levels of TCP, had no effects on FTCP brain levels, suggesting that metabolic drug-drug interactions may be less of a concern with FTCP than with TCP. In vitro uptake experiments in prisms prepared from hypothalamus or striatum revealed that TCP and FTCP are both potent inhibitors of norepinephrine (NE) uptake; FTCP is a more potent inhibitor of 5-HT uptake than is TCP. FTCP is a more potent releaser of 5-HT than is TCP. Drug Dev.

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Implications of chirality and geometric isomerism in some psychoactive drugs and their metabolites

Coutts

Baker

1989

Chirality

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Many drugs contain a chiral centre, or such a centre is introduced during metabolism of the drug in man and in animals. If a single chiral centre is present, the drug will normally exist as a mixture of two enantiomers, of which one may have quite different pharmacologic and/or toxic effects than the other. Chiral drugs that are used in psychiatry, and some other pharmacologically related drugs are identified, and the implications of the presence of one or two chiral centres in these drugs are discussed. Differences in pharmacologic properties of drug and metabolite enantiomers are identified and discussed. Also reviewed are the properties of some drugs used in psychiatry that both are chiral and display geometric isomerism.

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Detection and quantitation of a ring-hydroxylated metabolite of the antidepressant drug tranylcypromine

Cited by 25 publications

References 13 publications

4-fluorotranylcypromine, a novel monoamine oxidase inhibitor: Neurochemical effects in rat brain after short- and long-term administration

4-fluorotranylcypromine, a novel monoamine oxidase inhibitor: Neurochemical effects in rat brain after short- and long-term administration

4‐fluorotranylcypromine, a novel monoamine oxidase inhibitor: Neurochemical effects in rat brain after short‐ and long‐term administration

Implications of chirality and geometric isomerism in some psychoactive drugs and their metabolites

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