Metabolism of diazepam in dogs: Transformation to oxazepam

Ruelius, Hans W.; Lee, Jean M.; Alburn, Harvey E.

doi:10.1016/0003-9861(65)90199-2

Cited by 49 publications

(4 citation statements)

References 9 publications

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“…Hence, it is not known whether other metabolic pathways are responsible for the continuous metabolism of diazepam. Additional metabolic pathways such as C5 ring-hydroxylation , 22 or diazepine ring-opening and N-deethylation 23 to form benzophenone, or N4 oxidation, 24 all have been reported in other species, but standards were unavailable to authenticate these routes. Purified human CYP2A6 has been shown to catalyze the ECOD activity.…”

Section: Discussionmentioning

confidence: 99%

Xenobiotic Metabolism by Cultured Primary Porcine Hepatocytes

et al. 2000

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Considering the large yield of viable cells comparable to human liver, primary porcine hepatocytes offer a valuable resource for constructing a bioartificial liver device. In this study, the ability of cultured primary porcine hepatocytes to detoxify xenobiotics has been examined using various known substrates of cytochrome P450 isoenzymes and UDP-glucuronosyltransferases. Present investigation demonstrated the stability of the isoenzymes responsible for the metabolism of diazepam in native state and stabilization of other isoenzymes, as judged by ethoxycoumarin o-dealkylase (ECOD), ethoxyresorufin o-dealkylase (EROD), benzyloxyresorufin o-dealkylase (BROD), and pentoxyresorufin o-dealkylase (PROD) activities following induction in culture environment, for a period of 8 days. Resorufin O-dealkylase activities were found to be the most unstable and deteriorated within first 5 days in culture. These activities were restored following induction with 3-methylcholanthrene (3-MC) or sodium phenobarbital (PB) to 20-fold of 1 activity for EROD, and 60 and 174% of day 1 activity for PROD and BROD on day 8, respectively. Metabolism of methoxyresorufin was most strikingly increased following induction with 3-MC to approximately 60-fold of day 1 activity, on day 8. UDP-glucuronosyltransferase-dependent glucuronidation of phenol red, however, stayed intact during the course of our study without induction. Our study indicated that porcine hepatocytes in vitro maintain many important liver-specific functions including detoxification (steady state and inducibility).

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Section: Discussionmentioning

confidence: 99%

Xenobiotic Metabolism by Cultured Primary Porcine Hepatocytes

et al. 2000

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“…The inference is that a cyclopropylmethyl group is more resistant than a methyl group to oxidative dealkylation by human liver enzymes. The same may hold for dog liver microsomes; Ruelius and associates 13 observed very little 3-hydroxydiazepam formation from administered diazepam, whereas prazepam was hydroxylated extensively. 4 As a consequence of the different susceptibilities of prazepam and diazepam to biotransformation, these tranquilizers do not yield the same major metabolite in human urine.…”

Section: Discussionmentioning

confidence: 69%

Prazepam metabolism by man

DiCarlo¹,

Viau²,

Epps³

et al. 1970

Clin Pharma and Therapeutics

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“…Unchanged diazepam was found in human urine only after repeated administration over several weeks (16), and was never found in urine or feces of experimental animals (17)(18)(19)(20). The major metabolite of diazepam found in urine was a 4'-hydroxylated derivative.…”

Section: Plasmamentioning

confidence: 99%

Biotransformations and plasma-level curves of chiral 1,4-benzodiazepine-2-ones

Vukušić

Rendić

Fuks

1985

European Journal of Drug Metabolism and Pharmacokinetics

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Biotransformations of chiral 1,4-benzodiazepine-2-ones, (S)- and (R)-1 (7-chloro-1,3-dihydro-3 (S and R)-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one) in untreated and phenobarbital-pretreated rats were investigated. In urine, a 4'-oxygenated metabolite (compound 2) was identified as the biotransformation product from both enantiomers, (S)-2 being present in much higher amounts than (R)-2. Unchanged parent compounds were not found in urine. In plasma, 3'- and 4'-oxygenated metabolites were identified after administration of (S)-1 and (R)-1, respectively. The metabolite possessing an R-configuration was present in much lower amounts. The maximum concentrations of (R)-1 in plasma, following a single dose, was about 6 time as high as the maximum plasma concentration of (S)-1. Faster biotransformation and elimination of (S)-1 is assumed to be the explanation of these findings.

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Metabolism of diazepam in dogs: Transformation to oxazepam

Cited by 49 publications

References 9 publications

Xenobiotic Metabolism by Cultured Primary Porcine Hepatocytes

Xenobiotic Metabolism by Cultured Primary Porcine Hepatocytes

Prazepam metabolism by man

Biotransformations and plasma-level curves of chiral 1,4-benzodiazepine-2-ones

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