In vitro and in vivo interactions of .DELTA.8-tetrahydrocannabinol and its metabolites with hepatic microsomal drug metabolizing enzyme systems of mice.

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Abstract
Interactions of .DELTA.8-tetrahydrocannabinol (.DELTA.8-THC) and its metabolites, 11-hydroxy-.DELTA.8-THC, 11-oxo-.DELTA.8-THC and .DELTA.8-THC-11-oic acid, with hepatic microsomal drug metabolizing enzyme systems were studied in vitro and in vivo using mice. All the cannabinoids used produced a type I spectral change of cytochrome P-450 in hepatic microsomes. The apparent binding affinities (Ks) for .DELTA.8-THC, 11-hydroxy-.DELTA.8-THC, 11-oxo-.DELTA.8-THC and .DELTA.8-THC-11-oic acid were 5.2, 169.6, 33.2 and 148.8 .mu.M, respectively. .DELTA.8-THC, 11-oxo-.DELTA.8-THC and .DELTA.8-THC-11-oic acid (100 .mu.M) caused a significant stimulation of NADPH oxidation in vitro with microsomes. .DELTA.8-THC (20, 40 and 80 .mu.M) markedly inhibited p-nitroanisole O-demethylase and aniline hydroxylase in microsomes. 11-Hydroxy-.DELTA.8-THC and 11-oxo-.DELTA.8-THC also showed the inhibitory effect but to lesser extents. Single pretreatments with .DELTA.8-THC and 11-oxo-.DELTA.8-THC (30 mg/kg, i.v.) significantly decreased p-nitroanisole O-demethylase and aniline hydroxylase activities in hepatic microsomes, accompanying decreased cytochrome P-450 content in the case of .DELTA.8-THC. All pretreatments except for that with .DELTA.8-THC-11-oic acid showed a stimulatory effect on p-nitrophenol glucuronidation with hepatic microsomes, in contrast to an inhibitory effect in vitro.