Synthesis of Δ8-Tetrahydrocannabinol Glucuronide and Sulfate, and Their Metabolic Disposition in Rats

Abstract

8-Tetrahydrocannabinol (Δ8-THC) glucuronide and Δ8-THC sulfate were chemically synthesized as part of a study of the metabolic conjugation of Δ8-THC. Acidic and enzymatic hydrolyses of these conjugates were examined. Contrary to expectation, Δ8-THC glucuronide was resistant to both acidic and enzymatic hydrolyses. On the other hand, Δ8-THC sulfate was readily hydrolyzed by acid, but not at all by arylsulfatase. In addition, this sulfate ester uncompetitively inhibited the hydrolysis of p-nitrophenyl-sulfate by arylsulfatase. The biliary and urinary excretions of these conjugates were also studied. The Δ8-THC recovered after acid hydrolysis of the 24 hr bile of rats into which Δ8-THC glucuronide or sulfate had been administered accounted for about 43% and 10% of the dose, respectively. The glucuronide and sulfate of Δ8-THC both lacked the cataleptogenic effect of the parent compound. Δ8-THC sulfate exhibited a rather high acute toxicity (LD50 71 mg/kg i.v.), but the glucuronide caused no mortality up to a dose of 50 mg/kg i.v. in the mouse. © 1979, The Pharmaceutical Society of Japan. All rights reserved.