Abstract:
:Diazepam (DZ), N-desmethyl diazepam (NOR) and temazepam (TEM) were used as substrates in drug metabolism studies to characterize the changes in cytochrome P-450 mono-oxygenase pathways in hepatocytes isolated from cynomolgus monkeys, during culture for 6 days. Hepatocytes were incubated with DZ (20 microM), NOR (6 microM) or TEM (20 microM) for 3 hr at 3, 24, 48, 96 and 144 hr post-isolation in culture, and the profiles of disappearance of DZ, as substrate, and appearance of its metabolites determined. Major metabolites were NOR, TEM and oxazepam (OX). The kinetic profiles for the disappearance of DZ and the accumulation of metabolite were analysed using a four-compartment model and constants for the rates of formation of the metabolites were derived. There were significant changes during the period in culture for the rate constants of DZ demethylation, but no alteration in the 3-hydroxylation activities. Rates of DZ metabolism were unchanged during the initial 2 days in culture and well maintained for the subsequent 4 days, despite a fall in total cytochrome P-450 to 23% of initial values after 6 days. Cynomolgus monkey hepatocytes produce similar metabolite profiles for DZ to those found in man, both in vitro and in vivo, indicating that cynomolgus monkey hepatocytes may represent a relatively stable and valuable model of human drug metabolism.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Seddon T,Lockwood GF,Chenery RJdoi
10.1016/0006-2952(89)90547-9subject
Has Abstractpub_date
1989-08-15 00:00:00pages
2621-30issue
16eissn
0006-2952issn
1873-2968pii
0006-2952(89)90547-9journal_volume
38pub_type
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