Synthesis of Δ^8-Tetrahydrocannabinol Glucuronide and Sulfate, and Their Metabolic Disposition in Rats

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Δ^8-Tetrahydrocannabinol (Δ^8-THC) glucuronide and Δ^8-THC sulfate were chemically synthesized as part of a study of the metabolic conjugation of Δ^8-THC. Acidic and enzymatic hydrolyses of these conjugates were examined. Contrary to expectation, Δ^8-THC glucuronide was resistant to both acidic and enzymatic hydrolyses. On the other hand, Δ^8-THC sulfate was readily hydrolyzed by acid, but not at all by arylsulfatase. In addition, this sulfate ester uncompetitively inhibited the hydrolysis of p-nitrophenylsulfate by arylsulfatase. The biliary and urinary excretions of these conjugates were also studied. The Δ^8-THC recovered after acid hydrolysis of the 24 hr bile of rats into which Δ^8-THC glucuronide or sulfate had been administered accounted for about 43% and 10% of the dose, respectively. The glucuronide and sulfate of Δ^8-THC both lacked the cataleptogenic effect of the parent compound. Δ^8-THC sulfate exhibited a rather high acute toxicity (LD_<50> 71 mg/kg i.v.), but the glucuronide caused no mortality up to a dose of 50 mg/kg i.v. in the mouse.
公益社団法人日本薬学会の論文
1979-12-25