Exploring psychotherapeutic issues and agents in clinical practice
Drugs are nothing more than chemical substances composed of constituent atoms held together by chemical bonds. Carbon is the key component to the chemistry of life (Pace, 2001) and many drugs are carbon-based, but hydrogen bonding is especially important in biological systems and for understanding physicochemical properties of drug molecules. It is therefore not surprising that carbon–hydrogen bonds are commonly found in many organic compounds. If hydrogen were replaced in a drug molecule with something else, what effect would this have on the action of the drug? In this month’s column, I will discuss the concept of deuteration as it applies to drug development and describe several examples that pertain to psychiatric therapeutics.
What Is Deuteration?
Chemical elements in the periodic table are ordered according to their unique atomic number, which is the number of protons in their nucleus. Each element can have one or more isotopes, which are determined by the number of neutrons contained in their nucleus. The atomic mass of an element is defined as the sum of protons and neutrons.
Hydrogen, the first element in the periodic table, has three isotopes: protium, deuterium, and tritium. Each isotope has a single proton in its nucleus, but they are distinguished by the number of neutrons. Protium is the most common isotope and has an atomic mass of 1 because it has no neutrons. By contrast, tritium contains two neutrons, giving it an atomic mass of 3, and it is radioactive. Tritium is rarely found naturally, but is produced through various nuclear reactions. Deuterium is stable, naturally occurring, and non-radioactive. Because it has an atomic mass of 2 (having one proton and one neutron), deuterium is sometimes referred to as “heavy hydrogen.” The hydrogen ordinarily contained in organic compounds, such as water and drug molecules, is protium. Heavy water refers to a type of water in which a larger proportion of protium isotopes are replaced by deuterium isotopes.
Deuteration refers to the selective replacement of protium hydrogen atoms in small-molecule drugs with deuterium (Harbeson & Tung, 2014). Deuterated drugs are also referred to as “heavy drugs” (Katsnelson, 2013). With regard to the size and shape of the molecule, a deuterated compound is similar to an all-protium compound. Although minor differences in the physical properties of deuterated compounds can be detected, these differences do not appear to significantly affect the affinity or selectivity of the compound at its target. Due to the greater atomic mass of deuterium, however, cleavage of carbon–deuterium bonds requires greater energy than cleavage of protium bonds. For this reason, the metabolism of drugs involving enzyme pathways that cleave carbon–hydrogen bonds may be influenced when deuterium is substituted for protium.
Effect of Deuteration on Drug Metabolism
Tyrosine, an amino acid present in protein, is a precursor for the synthesis of catecholamine neurotransmitters (i.e., dopamine, nor-epinephrine, and epinephrine). When tyrosine-containing foods are aged, fermented, ripened, or spoiled, tyrosine is converted to the chemical product tyramine. Tyramine is structurally similar to norepinephrine and epinephrine, and has similar physiological “pressor” effects (i.e., increased heart rate, increased blood pressure, and vasoconstriction). Ingested tyramine ordinarily is metabolized by the enzyme monoamine oxidase (MAO) present in the gut and liver. MAO inhibitor drugs can be associated with the development of severe hypertension when tyramine-containing foods are ingested.
In one of the earliest experimental demonstrations of the effect of deuteration on drug metabolism, Belleau, Burba, Pindell, and Reiffenstein (1961) determined in cats that deuterated tyramine was metabolized more slowly than non-deuterated tyramine. As a result, deuterated tyramine was associated with a more prolonged pressor response.
Tetrabenazine (Xenazine®), approved by the U.S. Food and Drug Administration (FDA) for the treatment of chorea in Huntington disease, has been demonstrated to be effective at reducing motor symptoms in patients with tardive dyskinesia (Ondo, Hanna, & Jankovic, 1999). This drug inhibits the neuronal release of dopamine. Potentially severe adverse effects of tetrabenazine include nausea, sedation, fatigue, depression, anxiety, Parkinsonian effects, akathisia, and orthostatic hypotension. Side effects may be related to maximum concentrations of the parent drug, as well as variable levels of its active metabolites that are further metabolized by the cytochrome P450-2D6 (CYP2D6) hepatic enzyme (Harbeson & Tung, 2014).
In Phase 1 studies, the maximum concentration of deuterated tetrabenazine (i.e., SD-809) after oral administration is roughly similar to tetrabenazine (Harbeson & Tung, 2014). The metabolism of SD-809 active metabolites by CYP2D6 is reduced, however, resulting in a longer half-life and greater drug exposure. Smaller oral doses of SD-809 may therefore achieve a similar degree of drug exposure with a lower maximum concentration. If so, the tolerability of SD-809 may be better than for tetrabenazine. SD-809 is currently being evaluated in placebo-controlled Phase 3 studies for the treatment of Huntington disease (NCT01795859 and NCT01897896) and tardive dyskinesia (NCT02195700, NCT02291861, and NCT02198794).
The serotonin reuptake inhibitor drug paroxetine (Paxil®/Brisdelle®) is approved by the FDA for the treatment of major depression, various anxiety disorders, premenstrual dysphoric disorder, and menopausal hot flashes. Paroxetine is not only metabolized by CYP2D6, but also inhibits CYP2D6 enzyme activity. As a result, its metabolic clearance may be reduced over time. Deuterated paroxetine (i.e., CTP-347) has similar effects on serotonin reuptake compared to paroxetine, but Phase 1 studies found that CTP-347 is metabolized more rapidly than paroxetine (Uttamsingh et al., 2015). The Phase 1 studies also demonstrated that CTP-347 was significantly less likely to inhibit the CYP2D6-mediated metabolism of the drug dextromethorphan. These findings suggest that CTP-347 may be less prone to CYP2D6-mediated drug–drug interactions. No further clinical development of CTP-347 beyond the Phase 1 studies has been reported.
Pharmacology and Clinical Use of Dextromethorphan/Quinidine
The fixed-dose combination drug dextromethorphan/quinidine (i.e., AVP-923; Nuedexta®) has been approved by the FDA for the treatment of pseudobulbar affect (PBA) (Yang & Deeks, 2015). PBA is characterized by involuntary uncontrollable crying and/or laughter, and is commonly seen in patients with neurodegenerative conditions such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer’s disease, stroke, and traumatic brain injury. Antidepressant drugs are recommended, but none are approved for this indication. Dextromethorphan, the d-stereoisomer of the chiral racemate drug methorphan, is a cough suppressant at low doses and has dissociative and hallucinogenic effects at higher doses. This drug has a constellation of effects on various receptor systems, including N-methyl-D-aspartate, non-opioid sigma, nicotinic acetylcholine, and opioid receptors, as well as on serotonin and norepinephrine transporters (Lauterbach, 2012). These pharmacological effects have provided a justification for the use of dextromethorphan in patients with neurodegenerative disorders associated with PBA (Brooks et al., 2004). Dextromethorphan alone is not effective; however, it is extensively and rapidly metabolized, mainly by CYP2D6 and, to a lesser extent, by CYP3A4.
Bioavailability of dextromethorphan is greater in individuals who are genetically predisposed to CYP2D6 poor metabolism (Howland, 2006) compared to CYP2D6 extensive metabolizers (Pope et al., 2004). The cardiovascular anti-arrhythmic drug quinidine (Quinidex®), a stereoisomer of quinine (Qualaquin®), is a strong inhibitor of CYP2D6. Adding low-dose quinidine increases the effective bioavailability of dextromethorphan (Zhang, Britto, Valderhaug, Wedlund, & Smith, 1992).
A large Phase 3 placebo-controlled trial found that AVP-923 was significantly effective in patients with diabetic neuropathic pain (Shaibani, Pope, Thisted, & Hepner, 2012). Phase 2 studies of AVP-923 have been completed for Levodopa-induced dyskinesia in Parkinson’s disease (NCT01767129) and for agitation in Alzheimer’s disease (NCT01584440), but no results have been reported. Phase 2 studies for autism spectrum disorder (NCT01630811) and migraine (NCT02176018) are in progress. Pharmacological effects of dextromethorphan suggest it may be a viable antidepressant drug (Lauterbach, 2012), and a Phase 2 trial of AVP-923 for treatment-resistant major depression is being conducted (NCT01882829).
The drug AVP-786 (formerly known as CTP-786) is a combination of deuterated dextromethorphan and ultra-low dose quinidine (Harbeson & Tung, 2014). Similar plasma levels of dextromethorphan and deuterated dextromethorphan are achieved after oral administration of AVP-923 and AVP-786, respectively, even though AVP-786 contains a substantially lower quinidine dose. As a result, the potential cardiotoxicity associated with quinidine may be minimized with AVP-786. A placebo-controlled Phase 2 trial of AVP-786 for treatment-resistant major depression is in progress (NCT02153502). Phase 3 studies of AVP-786 for agitation in Alzheimer’s disease (NCT02442778 and NCT02442765) and a Phase 2 study for negative symptoms of schizophrenia (NCT02477670) are planned.
Deuterium appears to have little or no toxicity based on animal and human studies (Harbeson & Tung, 2014). Because forensic toxicology laboratories use deuterated analogues of drugs for qualitative and quantitative drug determination, introduction of deuterated therapeutics into clinical practice may have potentially serious analytical consequences (Kerrigan, 2009). The cytochrome P450 enzyme system is centrally important to the metabolism of most drugs. Deuteration of a drug is most likely to affect pharmacokinetic properties, such as metabolism, rather than its pharmacodynamic effects. Clinical studies of deuterated drugs are still necessary, even for drugs already in clinical use (i.e., paroxetine, tetrabenazine, and dextromethorphan), because the impact of deuterium substitution is unpredictable. Nurses should be familiar with the concept of deuteration, as this represents a novel approach to drug development that may have practical therapeutic and safety benefits for patients.
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