In Cannabis sativa, 9-Tetrahydrocannabinolic acid-A (9-THCA-A) is
the non-psychoactive precursor of 9-tetrahydrocannabinol (9-THC).
In fresh plant material, about 90% of the total 9-THC is available
as 9-THCA-A. When heated (smoked or baked), 9-THCA-A is only partially
converted to 9-THC and therefore,9-THCA-A can be detected in serum
and urine of cannabis consumers. The aim of the presented studywas
to identify the metabolites of9-THCA-A and to examineparticularlywhether
oral intake of9-THCA-A leads toin vivo formationof9-THC ina ratmodel.After
oral application of pure 9-THCA-A to rats (15mg/kg body mass), urine
samples were collected and metabolites were isolated and identified
by liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-tandem
mass spectrometry (LC-MS/MS) and high resolution LC-MS using time
of flight-mass spectrometry (TOF-MS) for accurate mass measurement.
For detection of 9-THC and its metabolites, urine extracts were
analyzed by gas chromatography-mass spectrometry (GC-MS). The identified
metabolites show that 9-THCA-A undergoes a hydroxylation in position
11 to 11-hydroxy-9-tetrahydrocannabinolic acid-A (11-OH-9-THCA-A),
which is further oxidized via the intermediate aldehyde 11-oxo-9-THCA-A
to 11-nor-9-carboxy- 9-tetrahydrocannabinolic acid-A (9-THCA-A-COOH).
Glucuronides of the parent compound and both main metabolites were
identified in the rat urine as well. Furthermore, 9-THCA-A undergoes
hydroxylation in position 8 to 8-alpha- and 8-betahydroxy- 9-tetrahydrocannabinolic
acid-A, respectively, (8α-Hydroxy-9-THCA-A and 8β-Hydroxy-9-THCA-A,
respectively) followed by dehydration. Both monohydroxylated metabolites
were further oxidized to their bishydroxylated forms. Several glucuronidation
conjugates of these metabolites were identified. In vivo conversion
of9-THCA-A to9-THCwas not observed.
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