A comparison between the metabolism of Δ¹-tetrahydrocannabinol by perfused lung and liver of rat and guinea-pig

Abstract

The metabolism of delta 1-tetrahydrocannabinol (delta 1-THC) by lung and liver of rat and guinea-pig have been studied by isolated perfused-organ techniques. Metabolites were identified by t.l.c. and mass fragmentography. Biotransformation in lungs showed a different quantitative pattern to the livers in both species. 4"-Hydroxy-delta 1-THC was a major metabolite in both rat and guinea-pig lung. 7-Hydroxy-delta 1-THC was another major metabolite in guinea-pig lung, but a minor one in rat lung. 6 alpha-Hydroxy-delta 1-THC and 6,7-dihydroxy-delta 1-THC were formed in small quantities in both species. Small amounts of 6 beta-hydroxy-delta 1-THC were detected in guinea-pig lung in addition to the metabolites mentioned. Livers of rat and guinea-pig formed 7-hydroxy-delta 1-THC as the most abundant metabolite together with minor amounts of 6 alpha-hydroxy- and 6,7-dihydroxy-delta 1-THC. 6 beta-Hydroxy-delta 1-THC was a minor liver metabolite in guinea-pig, and was found in rat only in trace amounts, together with delta 1-THC-6-one. No side-chain hydroxylated metabolites were detected in rat liver, while guinea-pig liver formed trace amounts of 3"-hydroxy- and 4"-hydroxy-delta 1-THC.

Hepatic Enzymes Relevant to the Disposition of (−)-∆9-Tetrahydrocannabinol (THC) and Its Psychoactive Metabolite, 11-OH-THC

“…While the contribution of CYP1A1 is negligible in the liver, CYP1A1, the major DME in the lung (Zhang et al, 2006), may be important for cannabinoid lung disposition. There is no current direct evidence of lung cannabinoid metabolism in human; however, biotransformation of THC to 11-OH-THC is observed in rat lung homogenate and dog and guinea pig perfused lung (Nakazawa and Costa, 1971;Widman et al, 1975;Halldin et al, 1984). Since metabolism of THC by the human lung may be an important drug parameter in the cannabinoid PBPK, further studies need to be conducted to establish the contribution of lung metabolism to THC disposition, especially if CYP1A1 is induced by smoking marijuana.…”

Pharmacokinetics of 11-nor-9-Carboxy-Δ9-Tetrahydrocannabinol (CTHC) After Intravenous Administration of CTHC in Healthy Human Subjects

“…CTHC is formed as a secondary metabolite from 11‐hydroxy‐Δ 9 ‐tetrahydrocannabinol (Figure 1). Phase II metabolism forms the CTHC‐acyl‐glucuronide, 5 , 6 , 7 which is regarded as a major metabolic end product eliminated in urine 7 , 8 , 9 , 10 . Reports on CTHC excretion show that approximately 30–65% of the incorporated THC dose is excreted in feces as CTHC 7 , 11 , 12…”