Endocannabinoid metabolism 

The endocannabinoid system is a signalling system with multiple functions. It is a phylogenetically old system found in most species, indicating an essential role in vital functions. 

1. Synthesis endocannabinoids

The endocannabinoids anandamide and 2-AG are eicosanoids, a class of lipids derived from arachidonic acid. The synthetic pathway of anandamide involves two major steps 1) synthesis of N-arachidonyl-phosphatidylethanolamine (NAPE) from arachidonic acid and phosphatidylethanolamine catalyzed by the enzyme N-acyltransferase and 2) synthesis of anandamide and phosphatidic acid from NAPE via activity of N-arachidonyl-phosphatidylethanolamine phospholipase (NAPE-PLD). There are two pathways suggested for synthesis of 2-AG. In both pathways 2-AG is derived from phosphatidylinositol. These pathways either involve diacylglycerol lipase (DAGL) or phospholipase C. 

1.1. Functionality of endocannabinoids 

Since endocannabinoids act as intercellular messengers, the magnitude of effect of endocannabinoids is not only determined by binding affinity for CB receptors and rate of synthesis and release, but also by rate of removal from the extracellular space and rate of intracellular degradation.

Clearance of anandamide and 2-AG from the extracellular space is thought to be mediated by protein transporters. Intracellularly, fatty acid amide hydrolase (FAAH) is responsible for the degradation of anandamide, whereas monoacylglycerol lipase is involved in the degradation of 2-AG.

Thus, endocannabinoids are produced following an increase in intracellular Ca2+ or cAMP levels, and are inactivated when paracrine or autocrine cannabinoid activation is to be terminated via active transport mechanisms and intracellular degradation.

2. Removal and degradation of endocannabinoids 

Since endocannabinoids act as intercellular messengers, the magnitude of effect of endocannabinoids is not only determined by binding affinity for CB receptors and rate of synthesis and release, but also by rate of removal from the extracellular space and rate of intracellular degradation.

Clearance of anandamide and 2-AG from the extracellular space is thought to be mediated by protein transporters.

Intracellularly, fatty acid amide hydrolase (FAAH) is responsible for the degradation of anandamide, whereas monoacylglycerol lipase is involved in the degradation of 2-AG.11,16 Thus, endocannabinoids are produced following an increase in intracellular Ca2+ or cAMP levels, and are inactivated when paracrine or autocrine cannabinoid activation is to be terminated via active transport mechanisms and intracellular degradation. 

Source: The role of the endocannabinoid system in the regulation of energy balance(2010), PhD thesis by Koolman, Anna Hendrike  (RUG)

Metabolsim of palmitoylethanolamide 

Palmitoylethanolamide is currently as Normast® available as a molecule tested in many different states of chronic pain and inflammation.

It's clinical efficacy is impressive, as well as it's benign side effect profile and the easy in dosing multi-morbid patients, elderly patients and patients treated with different drugs.

As prurigo and pain states also frequently occur in patients suffering from liver and kidney insufficiency, the question of how to dose in those patients is a clinical relevant question. Although there have not been formal ADME studies of palmitoylethanolamide in human volunteers,  data on it's metabolism and degradation have been discussed, amongst others by Didier et al (2002).

From their work it becomes clear that dose reductions are not required, and Normast most probably can be prescribed and administered without problems to the above described patients to treat their pain and itch. This because the metabolism and degradation of PEA is a ubiquinous intracellular process.

We cite from his work. ^[1]

Cellular Removal And Degradation of palmitoylethanolamide

In vivo, the actions of PEA and anandamide are relatively short-lived,due to their rapid metabolism. As with PEA biosynthesis, the mechanism of cellular removal is at first sight similar to that for anandamide,namely cellular uptake followed by fatty acid amide hydrolase (FAAH)-catalysed hydrolysis to form palmitic acid and ethanolamine.

Whilst there is good evidence to surmise that the FAAH responsible for the hydrolysis of PEA is the same enzyme as that metabolising anandamide,the uptake processes for the two fatty acid amides are different.

Anandamide is taken up into cells predominantly by anenergy-independent mechanism of facilitated transport that at least in part is driven by the intracellular FAAH-catalysed removal ofaccumulated anandamide. This means that FAAH inhibition per se can reduce the rate of anandamide uptake. In contrast, at least 50% ofcellular PEA uptake is brought about by passive diffusion. And although the remaining uptake can be inhibited by anandamide,2-arachidonoylglycerol and related compounds, the presence of such a large uptake component due to passive diffusion means that inhibition of active PEA uptake is unlikely to be a viable pharmacological strategy for prolonging the pharmacological actions of this compound.

In contrast, there is good evidence to show that the pharmacological effects of exogenous anandamide in vivo are potentiated following inhibition of FAAH and it is thus reasonable to suggest that inhibition of this enzyme may also potentiate the pharmacologicaleffects of PEA.

Other sources related to metabolism of endocannabinoids such as PEA are available. ^{[2] [3] [4][5] [6]}

March 2011, Jan M. Keppel Hesselink, MD, PhD 

Appendix from Spigelman (2010) ^[7]

The endogenous lipid cannabinoids that bind to their receptors cannot be sequestered in vesicles and are therefore synthesized on demand and immediately released by neuronal tissues (Di Marzo et al. 1994; Stella et al. 1997). For example, N-arachidonoylethanolamine (anandamide, AEA) is mainly produced by a two-step enzymatic pathway involving calcium-dependent transacylase and phospholipase D (Cadas et al. 1997; Okamoto et al. 2004; Sugiura et al. 1996). Then, AEA either diffuses (Glaser et al. 2003) or is actively transported into cells (Patricelli and Cravatt 2001) and is rapidly degraded by the membrane-bound fatty acid amide hydrolase (FAAH) to arachidonic acid. Another endocannabinoid, 2-arachidonoyl glycerol (2-AG) is synthesized via the diacylglycerol lipase (DAGL)-mediated hydrolysis of diacylglycerol and metabolized primarily by monoacylglycerol lipase (MAGL) (Dinh et al. 2002). There is also evidence that FAAH and two recently characterized serine hydrolases (ABHD6 and ABHD12) may contribute to 2-AG metabolism (Blankman et al. 2007). Interestingly, FAAH is mainly a postsynaptic enzyme, whereas MAGL is localized to presynaptic axon terminals, suggesting possible differences in the functional roles for AEA and 2-AG (Gulyas et al. 2004). The brain levels of 2-AG are at least two orders of magnitude higher than AEA (Stella et al. 1997). Both AEA and 2-AG are cleared by a high-affinity, selective transporter, which has been characterized biochemically but not molecularly (Hillard et al. 2007;Moore et al. 2005). The biochemistry and metabolism of AEA and 2-AG, as well as other less-well-studied endocannabinoids, have been the subject of excellent reviews (Bisogno et al. 2005; Cravatt and Lichtman 2003; Di Marzo et al. 1999; Hillard 2000). 

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