Tetrahydrocannabinol metabolites

Lander N. et al., Total synthesis of cannabidiol and deltal-tetrahydrocannabinol metabolites, J. Chem. Soc. (Perkin 1), 1, 8-16, 1976. 

Y. Synthesis and biological activity of five tetrahydrocannabinol metabolites. J Am Chem Soc 94 7930-7931,1972. 

McArdle K, Mackie P, Pertwee R, Guy G, Whittle B, Hawksworth G (2001) Selective inhibition of delta-9-tetrahydrocannabinol metabolite formation by cannabidiol in vitro (abstract) in Proceedings of the BTS Annual Congress. Toxicology 168 133-134... 

Williams PL, Moffat AC (1980) Identification in human urine of delta-9-tetrahydrocannabi-nol-11-oic glucuronide a tetrahydrocannabinol metabolite. J Pharm Pharmacol 32 445-448... 

Y. Nakahara, H. Sekine, C.E. Cook, Confirmation of cannabis use. II. Determination of tetrahydrocannabinol metabolites in urine and plasma by HPLC with ECD, J. Anal. Toxicol., 1989, 13, 22-24. 

Szirmai M (1995) Total synthesis and analysis of major human urinary metabolites of dl-tetrahydrocannabinol, the principal psychoactive component of Cannabis sativa L. Dissertation, Uppsala University, Sweden... 

There are over 400 constituent compounds in marijuana. More than 60 of these are pharmacologically active cannabinoids, of which 4 are the most important. The most psychoactive is delta-9-tetrahydrocannabinol (A-9-THC). The other three important natural cannabinoids are A-8-THC, cannabinol and cannabidiol (Kumar et al., 2001). In addition, some of the metabolites of THC, such as 11-hydroxy-A-9-THC, are also psychoactive. As a consequence and contrary to many other drugs, the metabolism of THC in the liver does not decrease intoxication, rather it prolongs it. 

As it can be observed in Fig. 2, three out of the 16 investigated compounds, namely, heroin, lysergic acid diethylamide (LSD), and its metabolite 2-oxo, 3-hydroxy-LSD (O-H-LSD), were not detected in any wastewater sample. Two other target analytes, 6-acetyl morphine (6ACM) and A9-tetrahydrocannabinol (THC), were only present in influent wastewaters and with low detection frequencies. The most ubiquitous compounds, present in all influent and effluent wastewater samples analyzed, were the cocaine metabolite benzoylecgonine, and the amphetamine-like compounds ephedrine (EPH) and 3,4-methylenedioxymethamphetamine (MDMA or ecstasy). Cocaine, cocaethylene (CE, transesterification product of cocaine formed after the joint consumption of cocaine and ethanol), and morphine (MOR) were detected in all influent, but not in all effluent wastewaters (see Fig. 2). 

CS427 Masset, D., ]. H. Bourdon, ]. Arditti-Djiane, and ]. Jouglard. Impact of delta-9 tetrahydrocannabinol and its metabolites on the immune system. Acta Clin Belg Suppl 1999 1 39-43. 

Tetrahydrocannabinol is metabolized in the liver to form active metabolites which are further metabolized to inactive polar compounds these are excreted in the urine. Some metabolites are excreted into the bile and then recycled via the enterohepatic circulation. Because of their high lipophilicity, most active metabolites are widely distributed in fat deposits and the brain, from which sources they are only slowly eliminated. The half-life of elimination for many of the active metabolites has been calculated to be approximately 30 hours. Accordingly, accumulation occurs with regular, chronic dosing. Traces of the cannabinoids can be detected in the blood and urine of users for many days after the last administration. There is some evidence of metabolic tolerance occurring after chronic use of the drug. THC and related cannabinoids readily penetrate the placental barrier and may possibly detrimentally affect foetal development. 

Figure 7.16 Capillary supercritical fluid chromatogram of tetrahydrocannabinol and six metabolites. Conditions supercritical C02 at 120°C 15-m x 50-/itn ID SE-33 column density programmed from 0.40 g/ml after a 7-min hold to 0.56 g/ml at 0.01 g/ml/min FID at 280°C. (Reprinted from Ref. 27, J. Chromatogr. Sci. by permission of Preston Publications, a division of Preston Industries.)...

Later et al. analyzed steroids, antibiotics, and cannabinoids on a methylpolysiloxane (SE-33) capillary column using carbon dioxide as the mobile phase [27]. Figure 7.16 shows the separation of tetrahydrocannabinol and its six metabolites in less than 20 min. 

THC undergoes metabolic degradation in the liver, where it is hydroxylated to 11-hydroxy tetrahydrocannabinol (THC-llOH). The latter, still with psychoactive activity, is oxidized to A9-THC-COOH, an inactive metabolite which is conjugated as 1 l-nor-A9-tetrahydrocannabinol-9-carboxy-glucuronide (A9-THC-COOH-glu), more hydrophilic metabolite and therefore easily excreted in the urine [32],... 

Pharmacological and metabolic studies on cannabinoids (Fig. 1) have suffered from a lack of knowledge of their physico-chemical properties and the insensitivity of assays of A -tetrahydrocannabinol 1, and its metabolites in biological fluids. Unambiguous, sensitive, specific and accurate quantification is required for forensic toxicology and pharmacokinetic studies which can be correlated with the time course of the psychoactive effects (2). 

Clinical investigations of A -tetrahydrocannabinol (4,5) and ll-hydroxy-A -tetrahydrocannabinol (6) have relied upon analysis by radioactive labeling. However, the study of distribution, metabolism and excretion of the drug and its metabolites under chronic or "street" conditions demands nonradioactive analytical procedures. When plasma suspensions of l c-A -tetrahydrocan-nabinol were administered intravenously to three dogs at doses of 0.1 - 2.0 mg/kg and plasma levels of 1 were followed for up to 7000 minutes, no significant differences were seen in 1 plasma levels as determined by liquid scintillation and electron capture detection (GLC) after HPLC collection. 

The monohydroxylated metabolites had large retention volumes (> 15 ml) on the normal phase column when 20% chloroform in heptane was the solvent and could be completely separated from tetrahydrocannabinol on this system. They were resolved from each other with a more polar solvent, 80% chloroform in heptane. 

The normal phase HPLC (20% chloroform in heptane) could separate A9-tetrahydrocannabinol from monohydrox-ylated metabolites and from 11-hydroxy-A tetrahydrocannabinol. However, a minor overlap could be avoided by collecting the tetrahydrocannabinol 1 in a slightly narrower volume range. The prior heptane extraction of alkalinized plasma had separated these non-polar constituents from any acidic metabolite. This separation of plasma extracts and normal phase HPLC collection of volumes in the appropriate range resulted in a substantial reduction in GLC background from plasma components for derivatized tetrahydrocannabinol analyzed with electron capture (63 1) detection. 

The large instability of A -tetrahydrocannabinol in acid solution (16,18), implies that the drug may be significantly degraded in the normal stomach. Again, this intimates that oral administration may not be an optimum route on which to establish dose-response correlations. Furthermore, the choice of a cannabinoid as an internal standard is very critical since it must not give any interference with the other related compounds, unless a HPLC purification step is included in the procedure. Cannabinol which, at times, has been taken as a possible metabolite (19-21) of A9-tetrahy-drocannabinol, may only be an artifact of the analytical procedure since disproportionation of 1 occurs readily. 

Quantitation of A9-Tetrahydrocannabinol and Its Metabolites in Human Urine by Probability Based Matching GC/MS... 

HPLC Analysis of a 9-Tetrahydrocannabinol and Metabolites in Biological Fluids... 

Metabolism of I in humans has been studied by several groups (5-8) with findings that 11-hydroxy A9 -tetrahydrocannabinol (V) and ll-nor-A9-tetrahydrocanni-binol-9-carboxylic acid (VI) are the principal metabolites. ... 

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