Phytocannabinoid drug-drug interactions and their clinical implications

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Abstract

Cannabis is a plant with a long history of human pharmacological use, both for recreational purposes and as a medicinal remedy. Many potential modern medical applications for cannabis have been proposed and are currently under investigation. However, its rich chemical content implies many possible physiological actions. As the use of medicinal cannabis has gained significant attention over the past few years, it is very important to understand phytocannabinoid dispositions within the human body, and especially their metabolic pathways. Even though the complex metabolism of phytocannabinoids poses many challenges, a more thorough understanding generates many opportunities, especially regarding possible drug-drug interactions (DDIs). Within this context, computer simulations are most commonly used for predicting substrates and inhibitors of metabolic enzymes. These predictions can assist to identify metabolic pathways by understanding individual CYP isoform specificities to a given molecule, which can help to predict potential enzyme inhibitions and DDIs. The reported in vivo Phase I and Phase II metabolisms of various phytocannabinoids are herein reviewed, accompanied by a parallel in silico analysis of their predicted metabolism, highlighting the clinical importance of such understanding in terms of DDIs and clinical outcomes.

Introduction

Cannabis is a plant with a long history of human pharmacological use, both for recreational purposes and as a medicinal remedy (Balabanova, Parsche, & Pirsig, 1992; ElSohly & Slade, 2005; Grotenhermen, 2007; Hazekamp & Grotenhermen, 2010; Liskow, 1973; Raharjo & Verpoorte, 2004; Sharma, Murthy, & Bharath, 2012). Its two major chemical constituents are cannabidiol (CBD), the definitive structure of which was reported in 1963 (Mechoulam & Shvo, 1963) and Δ-9-trans-tetrahydrocannabinol (THC) which was elucidated in the following year (Gaoni & Mechoulam, 1964). These early discoveries opened the way for exploration of many similar plant-specific compounds, which were ultimately termed collectively as “phytocannabinoids” (Pate, 1999) to differentiate them from the endogenous “endocannabinoids” discovered during the 1990s (Mechoulam, Hanus, Pertwee, & Howlett, 2014). The most important psychoactive phytocannabinoid is THC, usually accompanied by varying amounts of CBD, a relatively non-psychoactive compound which is able to modulate some of the psychotropic effects of THC (Eichler et al., 2012). THC is useful for several clinical indications, such as pain management, and as an antiemetic, antispasmodic and appetite stimulant (Clark, Ware, Yazer, Murray, & Lynch, 2004; Eichler et al., 2012; ElSohly, 2002; ElSohly & Slade, 2005; Furler, Einarson, Millson, Walmsley, & Bendayan, 2004; Russo, 2001, Russo, 2002; Tramer et al., 2001; Ware, Adams, & Guy, 2005; Wood, 2004). The use of high-THC content cannabis for glaucoma and asthma has been suggested (Appendino, Chianese, & Taglialatela-Scafati, 2011; Sharma et al., 2012) and the whole plant extract (as Epidiolex®) of a high-CBD Cannabis variety has recently been approved (FDANewsRelease, 2018; Gaston & Friedman, 2017; Koltai, Poulin, & Namdar, 2019) by the United States Food and Drug Administration (U.S. FDA) for application to certain forms of epilepsy.

Currently, there exist several cannabis inspired or based commercial pharmaceutical products for a range of medical indications. Dronabinol is synthetic THC and has been sold for decades as the pharmaceutical product Marinol®. It is indicated to ameliorate anorexia in patients with AIDS, and for the treatment of nausea and vomiting in cancer chemotherapy patients not responding to conventional antiemetic treatments (Dronabinol, 2019; Rong et al., 2018). Nabilone is a synthetic analog of THC which is marketed as the pharmaceutical product Cesamet®. Although distinct in molecular structure from THC, nabilone mimics THC pharmacological activity and is approved by the U.S. FDA for treatment of the same indications (Nabilone, 2019). Sativex® (generically known as “nabiximols”) is a whole plant extract derived from Cannabis which is used for the treatment of neuropathic pain originating from multiple sclerosis, and for intractable cancer pain. It is marketed as an oro-mucosal pump spray having a 1:1 ratio of THC:CBD (Nabiximols, 2019; Rong et al., 2018). Many other potential applications for cannabis have been proposed, and are currently under investigation (Medical Cannabis, 2019; Sharma et al., 2012; Zou & Kumar, 2018).

The rich chemical content of the Cannabis plant (more than 400 compounds) illustrates the possibility of a wide range of pharmacological applications (Sharma et al., 2012), as well as many possible interactions. The most well-known and most specific class of these compounds is the C21/22 terpenophenolic phytocannabinoids (ElSohly & Slade, 2005; Mechoulam & Gaoni, 1967). These compounds are classified according to their molecular structure into several types, for which THC, CBD, cannabichromene (CBC), cannabigerol (CBG) and their homologues are representative.

Interestingly, in fresh Cannabis plant extracts, these terpenophenolic phytocannabinoids per se are not abundantly present, but rather found mostly as their 2-carboxy form (Fig. 1), which are the only demonstrated biogenetic compounds. Of these, Δ-9-trans-tetrahydrocannabinolic acid (THCA) represents the majority of the collective total phytocannabinoids contained within tropically derived plants, which accumulate mainly on the flowers (exceeding a dry weight content of 20% in some recreational varieties) and leaves, and apparently serve plant protective functions (Moreno-Sanz, 2016; Pate, 1994). Cannabidiolic acid (CBDA) is predominant (at more than 10% by dry weight in a few medical strains) in plants from temperate regions. Neither compound is psychoactive per se, but both of these carboxylated compounds can be transformed into THC and CBD, respectively, through a degradative process which occurs slowly upon storage, but rapidly upon heating (Grotenhermen, 2003; Moreno-Sanz, 2016). Under field conditions, and with mild processing and cold storage, the extent of this decarboxylation is only nominal (~2–5%), which means that more carboxylic acid than phenolic forms are to be found in the oral fluid, serum, and urine of raw cannabis medical consumers (Dussy, Hamberg, Luginbühl, Schwerzmann, & Briellmann, 2005; Jung, Kempf, Mahler, & Weinmann, 2007; Moore, Rana, & Coulter, 2007; Moreno-Sanz, 2016). However, substantial to complete in situ decarboxylation occurs under the conditions of smoking or in baked goods.

Additionally, THC can be oxidized to cannabinol (CBN) via prolonged exposure to heat, oxygen and light (Russo, 2011). Hence, the presence of CBN indicates that a specimen is old, although most THC loss is due to the formation of polymers. The reported (Russo, 2011) pharmacological effect of CBN is mainly sedative, but this compound may also have application as an antibacterial, and may possibly decrease keratinocytes in cases of psoriasis.

Cannabichromenic acid (CBCA) is usually the third most abundant biogenetic phytocannabinoid in the Cannabis plant (McPartland & Russo, 2001), but that rank varies according to plant latitudinal origin, often being more abundant than CBDA in tropical specimens. As its decarboxylated form, CBC appears to potentiate some THC effects in vivo and has modest anti-nociceptive and anti-inflammatory effects (Hatoum, Davis, Elsohly, & Turner, 1981). Even though very little is known about its pharmacology, CBC has been shown to have the potential to stimulate the growth of brain cells and the ability to normalize gastrointestinal hypermotility (Aizpurua-Olaizola et al., 2016).

Least observed in the Cannabis plant is cannabigerolic acid (CBGA), the original biogenetic phytocannabinoid which metabolically yields CBDA, CBCA and THCA via their respective synthases (De Meijer & Hammond, 2005). Decarboxylation of the acid form (Wang et al., 2016) yields CBG, which has been shown to have anti-inflammatory, antibiotic and antifungal properties (Moreno-Sanz, 2016) and inhibits the growth of human oral epithelioid carcinoma cells (Baek et al., 1998). CBG has also been shown to have promising potential for the treatment of glaucoma, prostate carcinoma and inflammatory bowel disease (Aizpurua-Olaizola et al., 2016).

The aforementioned phytocannabinoids have a pentyl side-chain, but traces of methyl (Vree, Breimer, van Ginneken, & van Rossum, 1972) and minor amounts of propyl (De Meijer & Hammond, 2005) homologues also occur. The propyl homologues of CBD and THC, named cannabidivarin (CBDV) and Δ-9-trans-tetrahydrocannabivarin (THCV) respectively, are present in the plant at various ratios, depending on the specific Cannabis variety (Deiana et al., 2012). These compounds have not yet been studied as extensively as the other phytocannabinoids, but research shows that both THCV and CBDV may have therapeutic potential for reducing nausea (Rock, Sticht, Duncan, Stott, & Parker, 2013). Additionally, CBDV may have potential for the treatment of neuronal hyperexcitability, whereas THCV improves insulin sensitivity in obesity mouse models (Iannotti et al., 2014; Wargent et al., 2013). As little is known about these compounds, further studies regarding their pharmacological action and metabolic pathways are needed.

Recently, trace amounts of a novel seven-carbon THC homologue was isolated from Cannabis (Citti et al., 2019) and designated Δ-9-trans-tetrahydrocannabiphorol (THCP). Reported to be much more potent than the usual five-carbon THC, its similar pharmacological actions include hypomotility, analgesia, catalepsy and decreased rectal temperature.

Oral ingestion of baked goods, or inhalation of smoke/vapor, are the most common ways in which cannabis products are consumed (Grotenhermen, 2003; Moreno-Sanz, 2016). Compared to inhalation, the oral bioavailability of phytocannabinoids is relatively low (6–20%) due to a high first-pass metabolism within the liver (Ohlsson et al., 1980; Wall, Sadler, Brine, Taylor, & Perez-Reyes, 1983). Unlike inhaled phytocannabinoids, onset of psychoactive effects via oral ingestion is slow and varies from 30 minutes to occasionally over 2 h (Eichler et al., 2012), with the duration of action being more prolonged. This is due to the usually larger dose administered, slow gastro-intestinal absorption, and continued gut reabsorption (Eichler et al., 2012; Garrett & Hunt, 1977; Hollister et al., 1981; Lemberger et al., 1972; Ohlsson et al., 1980).

As mainstream use of cannabis grows, it is increasingly important to understand phytocannabinoid disposition within the human body, and especially its metabolic pathways. In a generic sense, the metabolic pathways operate under two broad categories: Phase I and Phase II. Phase I reactions include oxidation, reduction and hydrolysis, which increase the molecule’s hydrophilicity. Phase II metabolism involves conjugation reactions with endogenous hydrophilic compounds to either increase water solubility or inhibit pharmacological activity (Kirchmair et al., 2015, Kirchmair et al., 2013; Tyzack & Glen, 2014; Tyzack & Kirchmair, 2019). These reactions include glucuronidation, sulfation, amino acid conjugation, acetylation, methylation and glutathione conjugation. Even though the complex metabolism of phytocannabinoids poses many challenges, a more thorough understanding generates many opportunities, especially with regard to the investigation (Testa, Pedretti, & Vistoli, 2012) of possible drug-drug interactions (DDIs).

DDIs can lead to adverse drug reactions, with loss of, or increase in, efficacy due to altered systemic exposure. Therefore, as variations in drug response of the co-administered drugs can occur, it is important to evaluate potential drug interactions prior to market approval, as well as during the post-approval marketing period (Izzo et al., 2012). Consideration of these factors, combined with an increasing frequency of polypharmacy, has led regulatory agencies such as the U.S. FDA and the European Medicines Agency (EMA) to issue guidelines for industry to investigate the potential DDIs of new molecular entities. Guidance for studies of clinical drug interactions, in vitro metabolism, and transporter-mediated DDIs, as well as in silico analyses of DDIs, have been published (Prueksaritanont et al., 2013).

The application of in silico modelling and simulation within drug development is rapidly increasing in the R&D sector of the pharmaceutical industry (Duque et al., 2018; Silva, Duque, Davies, Löbenberg, & Ferraz, 2018). It has been suggested (Rostami-Hodjegan & Tucker, 2007) that such an approach could potentially represent up to 15% of R&D expenditures in the next 5–10 years. The in silico approach can be applied to all stages of the drug discovery and development process, from predicting the molecular properties of lead compounds to simulating clinical trials (Rostami-Hodjegan & Tucker, 2007). Within the context of metabolism prediction, in silico tools are most commonly used for predicting substrates and inhibitors of metabolic enzymes, sites of metabolism, and the structures of probable metabolites. These predictions can assist optimizations during the drug discovery process, helping to identify metabolic stability issues, in vivo half-lives and potentially toxic metabolites (Tyzack & Kirchmair, 2019). Furthermore, understanding the individual cytochrome P450 (CYP) isoform specificities of a given molecule can help to predict enzyme inhibitions and DDIs.

Phase I and Phase II enzymes are located in the endoplasmic reticulum of hepatocytes, hence that is where metabolic reactions such as Phase I hydroxylation by CYPs and Phase II glucuronidation occur (Elmes et al., 2019). Since phytocannabinoids are highly lipophilic molecules, a mechanism to facilitate their cytoplasmic transport from the cell membrane to the intracellular metabolic enzymes is needed (Morales, Hurst, & Reggio, 2017). It has been postulated that such trafficking is accomplished through soluble carrier proteins that cross the aqueous environments of the cytosol (Elmes et al., 2015, Elmes et al., 2019; Huang et al., 2016).

A recent report (Elmes et al., 2019) demonstrated that the candidates which are most likely to facilitate such transport in hepatocytes are fatty acid-binding proteins (FABPs), specifically FABP1, which has high expression levels in hepatocytes. Hence, based on this, it was concluded that FABP1 plays a major role in governing phytocannabinoid metabolism by transporting it to hepatic CYP enzymes. However, more studies are needed to understand the intracellular transport of phytocannabinoids. Studies with FABP1 knock-out mice (Elmes et al., 2015) revealed only a reduced effect on cannabinoid metabolism, suggesting that other cytoplasmic lipid-binding proteins may also be involved. In addition, sterol carrier protein-2, FABP2 and heat shock protein 70 have emerged as both endocannabinoid and phytocannabinoid transport proteins within cells (Elmes et al., 2015).

FABP1 may also serve as a previously unrecognized site of drug-drug-interactions. Numerous xenobiotics such as fibrates, warfarin, diazepam, flurbiprofen, and diclofenac have been shown (Elmes et al., 2019) to bind to FABP1 with comparable affinities to THC. Hence, these compounds may compete with phytocannabinoids for cellular uptake, leading to unpredictable pharmacological responses. Further studies are required to determine the clinical significance of competition for cellular uptake between phytocannabinoids and other drugs (Elmes et al., 2015, Elmes et al., 2019; Huang et al., 2016).

The reported in vivo Phase I and Phase II metabolisms of various phytocannabinoids is herein reviewed, accompanied by a parallel analysis of their predicted metabolisms in silico, highlighting the clinical importance of such understanding in terms of DDIs. A brief overview on the physiological mechanisms of action for phytocannabinoids is also presented.

Section snippets

Literature search

Databases such as Medline, Scopus, Google Scholar, Science Direct and SciFinder were systematically searched to identify relevant studies using key-words alone and in combination with each other, such as: THCA, THC, CBD, CBDA, CBC, CBCA, CBG, CBGA, THCV, CBDV, cannabinoids, metabolism, CYP isoforms, drug-drug interaction, oral administration, cannabis, in silico prediction, mechanism of action, cannabinoid receptors and endocannabinoid system. Priority was given to papers reporting human

Mechanisms of action

The first breakthrough for understanding the THC mechanism of action was in the late 1980s, with the discovery of a cannabinoid receptor in rat brain (Devane, Dysarz 3rd, Johnson, Melvin, & Howlett, 1988), now known as the cannabinoid receptor 1 (CB1). Receptors are generally activated by endogenous molecules, hence, there was a strong motivation to identify endogenous cannabinoids. The isolation and molecular structure determination of “anandamide” (an endogenous natural ligand of cannabinoid

Conclusions

Understanding phytocannabinoid metabolism is developing into a key factor within the drug development process, as a strategy to reduce the risk of costly late-stage project failure due to adverse ADMET properties. DDI knowledge is also of growing practical importance in order to avoid potential clinical complications arising from the increasingly widespread use of legal marijuana, both medically and recreationally. Alternatively, possible beneficial effects, including the opportunity to exploit

Statement

This work has not been published and is not under consideration for publication elsewhere.

Funding

Daniela Amara Silva is supported by the Alberta Innovates Graduate Student Scholarship. Opinions, interpretations, conclusions and recommendations are those of the author and not necessarily endorsed by the funding agency.

Declaration of Competing Interest

The authors declare no conflicts of interest.

Acknowledgments

The Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta acknowledges research funding from Blue Sky Biologicals, Applied Pharmaceutical Innovation and Xphyto Therapeutics.

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