Direct-acting Antiviral Interactions With Opioids, Alcohol or Illicit Drugs of Abuse in HCV-infected Patients

Kuntheavy Ing Lorenzini; François Girardin

Disclosures

Liver International. 2020;40(1):32-44. 

In This Article

Clinical Pharmacology of Substances of Abuse

The main PK/PD characteristics of selected substances of abuse are presented in Table 3.

Opioids

People often start with oral non-medical use of opioids, and move to more efficient routes of administration, such as insufflation, smoking or injection, and possibly initiate heroin use.[35] Data on Drug Abuse Trends showed a first increase in the misuse of opioids between 2004 and 2011.[36] Synthetic opioids, such as fentanyl, are major contributors to opioid-related overdoses.[37] The management of opioid use disorder (OUD) requires an integrated treatment that includes opioid substitution therapy (OST). Methadone was the first medication approved in this indication, and buprenorphine is also approved. Other available options include intravenous diamorphine (medical heroin), levomethadone and slow-release oral morphine.[38]

All opioids are metabolized through two major enzyme systems, CYP450 and UGT, but few of them are inhibitors or inducers of metabolizing enzymes or transporters; only methadone is identified as a CYP2D6[39] and P-gp inhibitor.[40] Excepted methadone, opioids are not expected to be significant perpetrator of CYP- or P-gp-mediated DDI with DAA.

Buprenorphine is a semisynthetic derivative of thebaine with partial opioid agonist properties, metabolized to norbuprenorphine by CYP3A (65%) and to a lesser extent by CYP2C8. Buprenorphine and norbuprenorphine undergo extensive Phase II metabolism by UGT, mainly UGT2B7 (>40%), followed by UGT1A1 and UGT1A3.[41]

Fentanyl is a synthetic opioid agonist, 50 times more potent than morphine, metabolized to norfentanyl by CYP3A and transported by P-gp.[41]

Heroin is rapidly metabolized by a sequential hydrolysis/deacetylation to 6-acetylmorphine (6-AM) and morphine.[42] The enzymatic metabolism is mediated mainly by human carboxylesterase 1 (hCE) and in part by hCE-2. Heroin has a very low affinity for μ-opioid receptors, and it acts as a highly lipophilic prodrug of its active metabolites 6-AM, morphine and morphine-6-glucuronide (M6G).[43]

Methadone is a synthetic opioid receptor agonist generally used as the racemic mixture of (R)- and (S)-methadone.[41] It is extensively metabolized by CYP450 enzymes, CYP2B6 being currently recognized as the major isoform in human.[44] Methadone is a P-gp substrate.[41]

Morphine is conjugated mainly by UGT2B7 to the inactive metabolite morphine-3-glucuronide (M3G) and, to a lesser extent, to the pharmacological active compound M6G.[41] UGT1A1, 1A3 and 1A9 are also involved but to a lesser extent.[43]

Oxycodone is a semisynthetic opioid that is mainly (80%) metabolized by CYP3A to noroxycodone, and to a lesser extent (10%) by CYP2D6 to oxymorphone, which is pharmacologically active.[41,45]

All opioids share a common profile of potential AEs that include among others tolerance and dependence, cognitive effects, sedation, delirium, constipation, vertigo, nausea and respiratory depression.[46,47] Reported AE also include cardiovascular effects, the most common being the prolongation of the QT interval, which can lead to torsades de pointes (TdP) and sudden death. The arrhythmogenicity of the main available opioids has been recently reviewed.[48] The website https://crediblemeds.org/, created and maintained by Arizona Education and Research on Therapeutics (AZCERT), is also a recommended source of information for drug-induced QT prolongation. This website defines three main categories of risk: known, possible and conditional risk.

Methadone is classified within the known risk category, buprenorphine within the possible risk category and fentanyl, morphine and oxycodone are not classified in any category. There have been many reports and studies showing the potential of methadone to induce QT interval prolongation and TdP even in low doses.[48] Buprenorphine at conventional doses, by itself, does not appear to produce clinically significant QT interval prolongation or polymorphic ventricular arrhythmia.[48]

Stimulants

Amphetamine and Derivatives. Amphetamine and its derivatives, which include 3,4-methylenedioxymethamphetamine (MDMA) or ecstasy, belong to the class of β-phenylethylamines and show chemical similarity with the catecholamine neurotransmitters, noradrenaline and dopamine.[49,50] After marijuana, these stimulants are the second most widely used group of illicit drugs worldwide. HCV infection is frequent among methamphetamine (N-methylated derivative of amphetamine) users as a consequence of unsafe injection methods, and as its use contributes to high-risk behaviours. One study in Veterans Affairs showed that 37% of HCV patients had a history of methamphetamine use. These patients were particularly prone to polysubstance use, alcohol and marijuana in particular.[51]

Amphetamine is metabolized to 4-hydroxyamphetamine via CYP2D6, while isoenzymes of the CYP2C subfamily mediate its deamination pathway. Amphetamine does not exert significant inhibition towards main CYP enzymes or P-gp.[52] Methamphetamine metabolism is also mediated by CYP2D6.[53] Amphetamine and methamphetamine are excreted through the kidneys.[52,53] MDMA metabolism occurs through two metabolic pathways, O-demethylation followed by catechol-O-methyltransferase (COMT)-catalysed methylation and/or glucuronide/sulphate conjugation; and N-dealkylation, deamination and oxidation to the corresponding benzoic acid derivatives conjugated with glycine. The involved enzymes are CYP2D6 and CYP1A2, and to a lesser extent CYP2B6 and CYP3A4. Moreover, MDMA is also a quasi-irreversible inhibitor of CYP2D6, through the formation of a metabolite-intermediate complex.[54]

As stimulants, amphetamines and derivatives can cause increases in blood pressure and heart rate, gastrointestinal symptoms such as nausea, vomiting and abdominal cramps.[49] After high dose and frequent methamphetamine use, psychotic episodes and neurotoxic effects such as memory deficits and impaired psychomotor can occur.[53] MDMA can produce panic attacks, delirium and brief psychotic episodes that usually resolve rapidly when the drug action wears off.[54]

Cathinones. Synthetic cathinones are derivatives of the parent compound cathinone, a naturally occurring psychostimulant found in the khat plant, Catha edulis.[55] The most common AEs associated with the use of cathinones include tachycardia, hypertension, anxiety/agitation, hallucinations/delusions, confusion and creatine kinase elevation.[56]

In vitro studies have shown that cathinones are mainly metabolized by CYP2D6, but the involvement of other enzymes is possible.[50] For example, mephedrone is mainly metabolized by CYP2D6.[57] A study in healthy users of khat showed that the use of this plant resulted in a CYP2D6 inhibition and a marginal effect on CYP3A4 and CYP2C19 activities, owing to competitive inhibition by cathinone.[58] Potential interactions between cathinones and DAA are limited.

Cocaine. Cocaine, the main alkaloid of Erythroxylum coca, is a powerful stimulant whose metabolism is mainly mediated by three esterases, pseudocholinesterase, human carboxylesterase-1 (hCE-1) and 2 (hCE-2). HCE-1 mediates the formation of benzoylecgonine, the main metabolite excreted in the urine. Pseudocholinesterase and hCE-2 catalyses the formation of ecgonine methyl ester.[59] Approximately, 85% to 90% of a dose are excreted in the urine, including 1% to 5% in unchanged form, and 75% to 90% of a dose as the metabolites benzoylecgonine and ecgonine methyl ester. Cocaine also undergoes oxidative metabolism by N-demethylation to pharmacologically active norcocaine. This metabolism is catalysed either by CYP3A4 or by a route involving both CYP and flavin-monooxygenases (2-step metabolism in the latter case).[59] Oxidative metabolism to norcocaine represents less than 10% of the biotransformation of cocaine.[60] Cocaine did not inhibit P-gp and BCRP in vitro.[40] The risk of interaction with DAA is, if any, very limited.

Cocaine blocks the presynaptic reuptake of norepinephrine and dopamine and acts as a powerful sympathomimetic agent. It has been associated with a variety of cardiac and other systemic complications. On the central nervous system, cocaine can cause cerebrovascular, neurological and psychological effects that include intracranial haemorrhage, seizures, movement disorders and psychiatric illness (such as psychosis, depression, decreased appetite).[61] Among the many complications exhibited by cocaine use, cardiovascular toxicities are very prominent and comprise hypertension, coronary spasm, arrhythmias, myocardial infarction, cardiomyopathy, atherosclerosis and coronary artery disease.[62] Pulmonary, hepatic and renal toxicities have also been reported.[61]

Various

Cannabinoids. The cannabis plant (Cannabis sativa) contains more than 100 different cannabinoids. Among them, delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are quantitatively important and of medical interest.[63] Commonly observed AEs with cannabinoids included: asthenia, balance problems, confusion, dizziness, dry mouth, fatigue, hallucinations, nausea, vomiting and drowsiness.[64]

THC is essentially stored in adipose tissue and is slowly released into the bloodstream, with a long terminal half-life of 25–36 hours.[65] THC metabolism is catalysed by CYP2C9 and CYP3A4. CBD is metabolized by CYP3A4.[66] At high concentrations, THC and CBD have demonstrated a potential inhibitory effect on CYP450 in vitro.[67–72] Some data suggested that cannabinoids might inhibit P-gp but at high concentrations that are probably not achieved in vivo.[40] Potential interactions with DAA have not been studied but probably appear limited without loss of DAA activity.

Ethanol. The vast majority of ethanol (>90%) is metabolized by liver alcohol dehydrogenase (ADH), whereas a small fraction (<6%) occurs via CYP2E1. These enzymes are inducible. Even though they account for a small percentage of ethanol metabolism, induction of CYP activity can increase ethanol elimination by more than 25%.[73]

The impact of ethanol on drug-metabolizing enzymes seems to differ after acute and chronic ingestion. Several in vitro studies have shown that some components of red wine inhibited CYP3A, and eventually CYP2C19 at high concentrations.[74] However, a study in healthy volunteers suggested the opposite. Indeed, acute red wine led to a 30%-40% decrease in the exposure of ciclosporine, a CYP3A substrate. The authors suggested that the mechanism could be decrease in ciclosporine solubility and absorption.[74] Consistent with in vitro data, a study in healthy volunteers showed that acute ethanol ingestion resulted in an average 30% increase in the area under the curve (AUC) of diazepam, a CYP2C19 (major pathway) and CYP3A substrate, although this observation was not confirmed by ulterior studies. Other clinical studies have shown the lack of significant impact of acute alcohol ingestion on the PKs of CYP3A substrates (triazolam, zolpidem, felodipine, verapamil, maraviroc, vardenafil).[75]

In an in vitro study, assessing the effects of chronic alcohol exposure on the expression of drug-metabolizing enzymes and drug transporters, ethanol strongly increased the mRNA expression of CYP2C19, CYP2E1 and ABCB1 after 1 and 3 weeks of exposure. Regarding ABCB1, this induction did not translate into an increase in efflux activity.[76] In another in vitro study, ethanol was shown to induce CYP3A4.[77] A study examining the liver biopsy from 12 patients with a history of excessive chronic alcohol consumption reported higher levels of CYP3A as compared to five patients with non-alcoholic hepatitis.[78] In a clinical study involving 20 individuals with moderate chronic alcohol consumption (average 2–3 drinks per day), the disposition of intravenous midazolam, a CYP3A substrate, was not altered as compared to 20 individuals without alcohol consumption. However, the oral availability of midazolam was reduced by 26% in the alcohol group, suggesting CYP3A induction at the small bowel level.[79] In another clinical study evaluating the PK of diazepam (CYP2C19 and CYP3A substrate), the AUC was lower in chronic alcohol drinkers than in healthy subjects, also suggesting an induced diazepam metabolism.[75] In conclusion, a modest induction of CYP3A could be expected in chronic alcohol users, but the change in drug PK may be confounded by the alteration of CYP enzyme activities as a result of chronic liver disease or mild cirrhosis rather than the presence of ethanol in the blood alone.[75]

Alcohol exhibits a dose-dependent effect on the central nervous system that can include disinhibition, sedation and respiratory depression. The cardiovascular effect can manifest as coronary vasodilatation after acute consumption, whereas chronic use can lead to increased blood pressure as well as arrhythmias and cardiomyopathy. Other effects associated with alcohol use are pancreatitis and liver diseases such as hepatitis and cirrhosis.[75]

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