Indolealkylamines: Biotransformations and Potential Drug–Drug Interactions

The AAPS Journal, Vol. 10, No. 2, June 2008 ( # 2008) DOI: 10.1208/s12248-008-9028-5 Review Article Indolealkylamines: Biotransformations and Potential Drug–Drug Interactions Ai-Ming Yu1,2 Received 23 January 2008; accepted 21 March 2008; published online 3 May 2008 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 βcarbolines 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. KEYWORDS: CYP2D6; drug interactions; indolealkylamine; metabolism; MAO; pharmacogenetics; tryptamine. INTRODUCTION Indolealkylamines (IAAs) are chemical derivatives of 5hydroxytryptamine (5-HT or serotonin), a monoamine neurotransmitter that modulates human mood and behaviors. Structurally, these compounds all possess an indole moiety and a basic nitrogen atom, which are connected by an alkyl chain usually of two carbons in length. Acting on the serotonergic system, some IAA agents such as ergotamine and triptan drugs (e.g. sumatriptan, naratriptan and almotriptan) (Fig. 1) have been successfully developed for antimigraine therapy (1–3). Many other IAA agents are important as widely abused substances although some show potential in psychopharmacotherapy. This group of IAA agents consists of lysergic acid amides such as D-lysergic acid diethylamide (LSD) and ergine (LSA), tryptamines such as psilocybin, N,N-dimethyltryptamine (DMT), bufotenine, 5-methoxy-N,N-dimethyltryptamine (5MeO-DMT) and 5-methoxy-N,N-diisopropyltryptamine (5MeO-DIPT), and β-carbolines such as harman, harmaline and harmine (4–6) (Fig. 2). Tryptamine (e.g. 5-MeO-DMT) and βcarboline (e.g. harmaline) derivatives are sometimes abused together. These substances are readily synthesized in underground laboratories, sold via the internet and abused particu1 Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, 541 Cooke Hall, Buffalo, New York 14260-1200, USA. 2 To whom correspondence should be addressed. (e-mail: aimingyu@ buffalo.edu) 1550-7416/08/0200-0242/0 # 2008 American Association of Pharmaceutical Scientists larly by teenagers and young adults. As an unscheduled substance, 5-MeO-DMT has even been referred to as the next generation designer drug to replace “ecstasy.” Cases of IAA intoxication have been continuously documented in the United States (7–9). Overdosing or combined abuse of IAA agents may cause severe or even fatal hyperserotonergic toxicity, namely “serotonin syndrome” (10,11). Of note, serotonin toxicity has become an important clinical problem over the last 15 years with the increasing use of psychotropic agents. A substantial body of research has revealed considerable variations in the metabolic and pharmacokinetic properties for therapeutic triptan agents, and provided adequate data to predict metabolic drug–drug interactions (DDIs) in clinical practice. In contrast, the metabolism of IAA drugs of abuse has not been fully characterized because of legal, ethical and safety issues associated in conducting human tests. For these agents, a stable metabolite, measured by a reliable analytical method, may serve as a better approach for forensic analysis. Many metabolic data were therefore obtained from animal studies, in which the discrepancy is obvious for some drugs (12,13). Furthermore, the specific role of individual drugmetabolizing enzymes including monoamine oxidases (MAO) and cytochrome P450 (P450 or CYP) enzymes (14) remains undefined, and mechanistic understanding of potential DDIs with other abused or therapeutic agents is mostly unknown. Increased knowledge in this area may advance our understanding of individual vulnerability to and/or protection from illicit drugs of abuse (15). This review, therefore, aims to describe our current understanding of the metabolism and potential DDIs of IAA drugs. 242 Indolealkylamines: Biotransformations and Potential Interactions 243 frovatriptan, it is 25 h (Table I). The sharp difference in elimination of different triptans is at least partly due to the marked difference in the metabolism of these drugs. Metabolism and Drug–Drug Interactions of Ergotamine and Triptans Fig. 1. Chemical structures of the 5-HT neurotransmitter and some antimigraine triptan drugs METABOLISM AND DRUG–DRUG INTERACTIONS OF THERAPEUTIC INDOLEALKYLAMINE DRUGS Mechanisms of Indolealkylamine Drugs for Antimigraine Therapy Ergotamine remains as a useful drug for acute treatment of severe migraine attacks (1,16). It is an ergot alkaloid originally isolated from fungus, and its pharmacological property in relieving migraine headache was shown about 70 years ago. Its antimigraine effect is generally attributed to the actions on 5-HT1B/1D receptors, whereas its side effects may be caused by the nonselective actions on a variety of other receptors including dopamine and 5-HT1A receptors. In contrast to the complex mode of actions of ergotamine, newer IAA antimigraine drugs, namely triptans, are much more selective for 5-HT1B and 5-HT1D receptors with high affinity (2,3). Sumatriptan is the first of these “new generation” IAA antimigraine agents that are better tolerated by patients. The pharmacokinetics properties of these triptans are quite diverse. For instance, the oral bioavailability of sumatriptan is about 14% whereas naratriptan is 63–74%. The elimination half-life of sumatriptan is 2 h whereas for Although ergotamine is known to be extensively metabolized in the liver, its metabolic pathways are largely undefined in humans. Nonetheless, there is good evidence from animal studies supporting that CYP3As are the major enzymes responsible for ergotamine metabolism (17). Indeed, CYP3A inhibitory drugs such as erythromycin and troleandomycin are known to decrease ergotamine metabolism and may lead to unwanted DDIs. To p (...truncated)