The metabolism of 2,3',4',5-tetrachlorobiphenyl (TCB) was compared using liver microsomes and six isoforms of cytochrome P450 purified from rats, guinea pigs and hamsters. In microsomal study, the following species differences were observed: 1) Untreated guinea pigs and hamsters but not rats can metabolize this TCB to 3-hydroxy- or 4-hydroxy-2,3',4',5-TCB, 2) Guinea pig microsomes showed only 3-hydroxylating activity, whereas hamster microsomes showed higher activity of 4-hydroxylation than that of 3-hydroxylation. In common with three species, the 3-hydroxylation was accelerated by phenobarbital. The 4-hydroxylation in rats and hamsters was increased by pretreatment with 3-methylcholanthrene and 3,3',4,4',5-pentachlorobiphenyl. The hydroxylation activities of liver microsomes from the three species could be explained by an involvement of different isoforms of cytochrome P450. In addition, it is apparent that hamster CYP1A2 as well as hamster CYP2A8 is involved in the 4-hydroxylation of 2,3',4',5-TCB although it has no activity for 2,2',5,5'-TCB.

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PubMedDate not supplied

Isolation and identification of urinary metabolites of oxycodone in rabbits.

Metabolism of oxycodone was studied in the rabbit and found to proceed through five metabolic pathways: O-demethylation, N-demethylation, N-oxidation, 6-keto reduction, and glucuronidation. Six urinary metabolites were isolated and identified in the unconjugated form: 14-hydroxydihydromorphinone, 14-hydroxydihydrocodeine, 14-hydroxydihydrocodeinone N-oxide (oxycodone N-oxide), 14-hydroxydihydroisocodeine, 14-hydroxydihydrocodeine N-oxide, and noroxycodone, together with unchanged oxycodone. Identification was made by means of various chromatographic and spectral comparisons with authentic samples. Oxycodone, 14-hydroxydihydromorphinone, 14-hydroxydihydrocodeine, 14-hydroxydihydroisocodeine, and noroxycodone were also identified as aglycons of conjugated metabolites.

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PubMedDate not supplied

Metabolic disposition of delta 8-tetrahydrocannabinol and its active metabolites, 11-hydroxy-delta 8-tetrahydrocannabinol and 11-oxo-delta 8-tetrahydrocannabinol, in mice.

Metabolic disposition of delta 8-tetrahydrocannabinol (delta 8-THC), 11-hydroxy-delta 8-THC (11-OH-delta 8-THC), and 11-oxo-delta 8-THC was studied in mouse blood, liver, and brain. After administration of these cannabinoids at a dose of 10 mg/kg iv, the concentration in blood declined biphasically. The biological half-lives of the slower phases were 32, 12, and 6 min, respectively, for delta 8-THC, 11-OH-delta 8-THC, and 11-oxo-delta 8-THC. 11-OH- and 11-oxo-delta 8-THC were also eliminated faster from brain than is delta 8-THC. The peak levels of 11-OH- and 11-oxo-delta 8-THC in brain were, however, higher (10.64 and 4.25 microgram/g, respectively) than that of delta 8-THC (3.48 microgram/g) at 0.5 min after the iv injection (10 mg/kg). These results indicate that 11-OH- and 11-oxo-delta 8-THC are distributed more readily from blood to brain in mice than is delta 8-THC, and explain the greater pharmacological activity of these metabolites, as reported previously. It was also interesting to note that a much higher level of 11-OH-delta 8-THC (3.27 microgram/g) was found in brain than in liver(0.74 microgram/g) and blood (0.29 microgram/ml) at 15 min after the injection of 11-oxo-delta 8-THC (10 microgram/kg, iv). In this case the levels of 11-OH-delta 8-THC were always higher than those of 11-oxo-delta 8-THC. The results suggest that 11-OH-delta 8-THC may play an important role in the pharmacological effects of 11-oxo-delta 8-THC. In additional experiments, SKF 525-A (25 mg/kg, ip) inhibited the metabolism of 11-OH-delta 8-THC to 11-oxo-delta 8-THC, supporting the previous suggestion that this oxidation, as well as the 11-hydroxylation of delta 8-THC, is mediated by the microsomal mono-oxygenase system.

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