Indolealkylamines: biotransformations and potential drug-drug interactions

Abstract

Indolealkylamine (IAA) drugs are 5-hydroxytryptamine (5-HT or serotonin) analogs that mainly act on the serotonin system. Some IAAs are clinically utilized for antimigraine therapy, whereas other substances are notable as drugs of abuse. In the clinical evaluation of antimigraine triptan drugs, studies on their biotransformations and pharmacokinetics would facilitate the understanding and prevention of unwanted drug-drug interactions (DDIs). A stable, principal metabolite of an IAA drug of abuse could serve as a useful biomarker in assessing intoxication of the IAA substance. Studies on the metabolism of IAA drugs of abuse including lysergic acid amides, tryptamine derivatives and beta-carbolines are therefore emerging. An important role for polymorphic cytochrome P450 2D6 (CYP2D6) in the metabolism of IAA drugs of abuse has been revealed by recent studies, suggesting that variations in IAA metabolism, pharmaco- or toxicokinetics and dynamics can arise from distinct CYP2D6 status, and CYP2D6 polymorphism may represent an additional risk factor in the use of these IAA drugs. Furthermore, DDIs with IAA agents could occur additively at the pharmaco/toxicokinetic and dynamic levels, leading to severe or even fatal serotonin toxicity. In this review, the metabolism and potential DDIs of these therapeutic and abused IAA drugs are described.

Fig. 1

Chemical structures of the 5-HT neurotransmitter and some antimigraine triptan drugs

Fig. 2

Chemical structures of some indolealkylamine drugs of abuse that consist of d-lysergic acid amides (e.g. LSD and LSA), tryptamine derivatives (e.g. psilocybin, DMT, bufotenine, 5-MeO-DMT and 5-MeO-DIPT), β-carbolines (e.g. harman, harmaline and harmine) and ibogaine

Fig. 3

Biotransformation of an antimigraine triptan drug, zolmitriptan. CYP1A2, cytochrome P450 1A2; MAO-A, monoamine oxidase A; ALDH, aldehyde dehydrogenase

Fig. 4

Metabolism of LSD. Note that the 2-oxo-3-hydroxy-LSD (2-oxo-3-HO-LSD) has been shown as a principal metabolite in the LSD-positive human urine samples

Fig. 5

Deamination of bufotenine and 5-MeO-DMT produces corresponding indole acetic acid derivatives. 5-MeO-DMT can be biotransformed to bufotenine through O-demethylation catalyzed primarily by CYP2D6, whereas bufotenine may be methylated to form 5-MeO-DMT

Fig. 6

Metabolism of 5-MeO-DIPT. The O-demethylation is primarily mediated by CYP2D6 and N-deisopropylation is catalyzed by CYP1A2, 2C8, 2C9, 2C19 and 3A4

Fig. 7

Biotransformations of psilocybin and psilocin. Psilocybin is dephosphorylated to produce psilocin that undergoes deamination and glucuronidation

Fig. 8

Metabolism of harmine. One major pathway is O-demethylation mediated by CYP2D6, 1A and 2C enzymes, and the metabolite harmol is subject to glucuronidation and sulfation. Hydroxylated harmine metabolites have also been identified, which occur at the 6- and 3- or 4-positions of harmine

Fig. 9

Serotonergic neurotransmission. Hyperserotonergic effects may be induced when a tryptamine derivative (5-HT receptor agonist) and a β-carboline (monoamine oxidase inhibitor) are used concurrently. In particular, the β-carboline can reduce the degradation of 5-HT neurotransmitter and inhibit the metabolism of tryptamine derivative