The fate of lysergic acid di[¹⁴C]ethylamide ([¹⁴C]LSD) in the rat, guinea pig and rhesus monkey and of [¹⁴C]iso-LSD in rat

The qualitative and quantitative aspects of the metabolism and elimination of [¹⁴C]LSD in the rat, guinea pig and rhesus monkey have been investigated. Rats given an i.p. dose (1 mg/kg) excreted 73% of the ¹⁴C in the faeces, 16% in the urine and 3.4% in the expired air as ¹⁴CO₂ in 96 hr. Guinea pigs similarly dosed, excreted 40% in the faeces, 28% (urine) and 18% (expired ¹⁴CO₂) in 96 hr. Rhesus monkeys (0.15 mg/kg i.m.) eliminated 39% of the ¹⁴C in the urine and 23% in the faeces in 96 hr. Extensive biliary excretion of [¹⁴C]LSD occurred in both the rat and guinea pig. Bile duct-cannulated rats excreted 68% of an i.v. dose (1.33 mg/kg) in the bile in 5 hr and the guinea pig 52% in 6 hr. [¹⁴C]LSD is almost completely metabolised by all three species and little unchanged drug is excreted. The metabolites identified were 13- and 14-hydroxy-LSD and their glucuronic acid conjugates. 2-oxo-LSD. de-ethyl LSD and a naphthostyril derivative. There occur, however, important species differences in the nature and amounts of the various metabolites. In the rat and guinea pig the major metabolites were the glucuronic acid conjugates of 13- and 14-hydroxy-LSD which were found in both urine and bile. The guinea pig excreted significant amounts of 2-oxo-LSD in urine and bile. De-ethyl LSD was a minor urinary metabolite in both species. The metabolism of LSD appeared to be more complicated in the rhesus monkey. The urine contained at least nine metabolites of which four were identified as follows: 13- and 14-hydroxy-LSD (as glucuronic acid conjugates) de-ethyl LSD and a naphthostyril derivative. Unlike the rat and guinea pig the glucuronic acid conjugates of 13- and 14-hydroxy-LSD were only present in small amounts. Of the remaining five unidentified metabolites, three were major. The biliary metabolites of [¹⁴C]iso-LSD in the rat have been studied and been shown to be similar to those produced from [¹⁴C]LSD, namely 13- and 14-hydroxy-iso-LSD and their glucuronic acid conjugates and 2-oxo-iso-LSD.