Introduction Of Experimental Pharmacology

Currently, there is a growing interest in the biology, chemistry, pharmacology, and toxicology of cannabinoids and in the development of potential cannabinoid medications. It is clear that the endogenous cannabinoid system plays a critical role in physiological and behavioral processes. Endogenous cannabinoid neurotransmit-ters, receptors, and transporters, synthetic cannabinoid agonists and antagonists, and cannabis-based extracts are the subject of extensive research. It is hoped that these agents might provide novel approaches to treat human diseases and disorders. The therapeutic usefulness of oral cannabinoids is being investigated for medicinal applications, including analgesia, treatment of acquired immunodeficiency syndrome (AIDS)-wasting disease, counteracting spasticity of motor diseases, and the prevention of emesis following chemotherapy, among others. Cannabis, also, is one of the oldest and most commonly abused drugs in the world, and its use may have consequences in terms of pathological and behavioral toxicity. For these reasons, it is important to understand cannabinoid pharmacokinetics and the disposition of cannabinoids into biological fluids and tissues. Understanding a drug's phar-macokinetics is essential to understanding the onset, magnitude, and duration of its pharmacodynamic effects.

Pharmacokinetics encompasses the absorption of cannabinoids following diverse routes of administration and from different drug formulations, the distribution of analytes throughout the body, the metabolism of cannabinoids by different tissues and organs, the elimination of cannabinoids from the body in the feces, urine, sweat, oral fluid, and hair, and how these processes change over time. In this chapter, we will review the many contributions to our understanding of cannabinoid pharmacokinetics from the 1970s and 1980s and the more recent research that expands upon this knowledge. Cannabinoid pharmacokinetic research has been especially challenging due to low analyte concentrations, rapid and extensive metabolism, and physicochemical characteristics that (1) hinder the separation of drugs of interest from biological matrices and from each other and (2) lower drug recovery due to adsorption of compounds of interest to multiple surfaces. Much of the earlier data utilized radio-labeled cannabinoids yielding highly sensitive but less specific measurement of individual cannabinoid analytes. Mass spectro-metric developments now permit highly sensitive and specific measurement of cannabinoids in a wide variety of biological matrices.

Cannabis sativa contains over 421 different chemical compounds, including over 60 cannabinoids (Claussen and Korte 1968; ElSohly et al. 1984; Turner et al. 1980). Cannabinoid plant chemistry is far more complex than pure A9-tetrahydrocannabinol (THC), and different effects maybe expected due to the presence of additional cannabinoids and other chemicals. In all, 18 different classes of chemicals, including nitrogenous compounds, amino acids, hydrocarbons, sugars, terpenes, and simple and fatty acids, contribute to cannabis' known pharmacological and toxicological properties. THC is usually present in cannabis plant material as a mixture of monocarboxylic acids that readily and efficiently decarboxylate upon heating. THC decomposes when exposed to air, heat, or light; exposure to acid can oxidize the compound to cannabinol, a much less potent cannabinoid. In addition, cannabis plants dried in the sun release variable amounts of THC through decarboxylation. During smoking, more than 2,000 compounds maybe produced by pyrolysis. The focus of this chapter will be THC, the primary psychoactive component of cannabis, its metabolites, 11-hydroxy-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-tetrahydrocannabinol (THCCOOH), and two other cannabinoids present in high concentrations, cannabidiol (CBD), a non-psychoactive agent with an interesting array of other activities, and cannabinol, which is approximately 10% as psychoactive as THC (Perez-Reyes et al. 1982). Mechoulam et al. elucidated the structure of THC after years of effort in 1964, opening the way for studies of the drug's pharmacokinetics (Mechoulam 1970). THC, containing no nitrogen but with two chiral centers in the trans-configuration, is described by two different numbering systems, the dibenzopyran or A9, and the monoterpene or A1 system; the dibenzopyran system is used throughout this chapter.

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