Prazepam Metabolism in the Rat

Viau, Jean-Paul; Epps, Joyce E.; Carlo, Frederick J. Di

doi:10.1002/jps.2600620422

Cited by 9 publications

(3 citation statements)

References 16 publications

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“…This substance disappears rapidly from the plasma with a short half-life.". l 6 In contrast to prazepam, however. clorazepate is converted to N-desmethyldiazepam in the acid milieu of the stomach" whereas prazepam is biotransformed to this metabolite by microsomal drug metabolizing enzymes' ' probably in the liver.…”

Section: Discussionmentioning

confidence: 92%

Concentrations of N‐descyclopropyl‐methylprazepam in whole‐blood, plasma, and milk after administration of prazepam to humans

Brodie¹,

Chasseaud²,

Taylor³

1981

Biopharm & Drug Disp

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After oral doses of 30 mg of prazepam to humans, N-descyclopropylmethylprazepam (desalkylprazepam, N-desmethyldiazepam) is the only major drug-related compound in plasma. Neither the parent drug, nor its major urinary metabolites were detected in plasma. The overall concentration-time profile of desalkylprazepam in the plasma of females was lower than, and significantly different (p less than 0.001) from that in the plasma of males. However, the mean peak desalkylprazepam concentrations in the plasma of females (265 ng ml-1 +/- 60 S.D.) were not significantly different (p greater than 0.05) from those in males (342 ng ml-1 +/- 60 S.D.). Concentrations declined in the plasma of either sex with similar half-lives (mean 60 h, range 37-93 h). Apparent plasma desalkylprazepam clearances were also similar (mean 60 h, range 37-93 h). Apparent plasma desalkylprazepam clearances were also similar (mean 1.09 l h-1), range 0.74-1.84 l h-1). At 12 h after the last of multiple doses of prazepam (60 mg d-1 for 3 days) to lactating women, mean plasma concentrations of desalkylprazepam were 823 ng ml-1 +/- 200 S.D. and declined with a mean half-life of about 60 h over the time-course studied. There was only slight uptake of desalkylprazepam into blood cells; plasma; whole blood concentration ratios were constant at about 1.6. Concentrations of desalkylprazepam in milk were low at about 10 per cent of the corresponding plasma levels (e.g. 86 ng ml-1 +/- 37 S.D. at 12 h). The data suggest that, expressed on a mg kg-1 basis, exposed neonates could receive about 4 per cent of the maternal dose of prazepam as desalkylprazepam.

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Section: Discussionmentioning

confidence: 92%

Concentrations of N‐descyclopropyl‐methylprazepam in whole‐blood, plasma, and milk after administration of prazepam to humans

Brodie¹,

Chasseaud²,

Taylor³

1981

Biopharm & Drug Disp

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“…Based on the metabolism of prazepam, hydroxylation most likely occurs at the 3‐position of the molecule, leading to 3‐hydroxycloniprazepam and to 3‐hydroxyclonazepam. Based on the metabolism of prazepam, the second hydroxylated clonazepam derivative is most likely 4′‐hydroxyclonazepam, and it can be assumed that it is not formed in humans to a significant extent . Formation of clonazepam and its metabolite 7‐aminoclonazepam is particularly important for the interpretation of analytical findings, as detection of these compounds might be misinterpreted as resulting from clonazepam intake.…”

Section: Resultsmentioning

confidence: 99%

Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines — an update comprising adinazolam, cloniprazepam, fonazepam, 3‐hydroxyphenazepam, metizolam and nitrazolam

et al. 2016

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Designer benzodiazepines represent an emerging class of new psychoactive substances. While other classes of new psychoactive substances such as cannabinoid receptor agonists and designer stimulants are mainly consumed for hedonistic reasons, designer benzodiazepines may also be consumed as 'self-medication' by persons suffering from anxiety or other psychiatric disorders or as stand-by 'antidote' by users of stimulant and hallucinogenic drugs. In the present study, five benzodiazepines (adinazolam, cloniprazepam, fonazepam, 3-hydroxyphenazepam and nitrazolam) and one thienodiazepine (metizolam) offered as 'research chemicals' on the Internet were characterized and their main in vitro phase I metabolites tentatively identified after incubation with pooled human liver microsomes. For all compounds, the structural formula declared by the vendor was confirmed by nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry (MS), liquid chromatography MS/MS and liquid chromatography quadrupole time-of-flight MS analysis. The detected in vitro phase I metabolites of adinazolam were N-desmethyladinazolam and N-didesmethyladinazolam. Metizolam showed a similar metabolism to other thienodiazepines comprising monohydroxylations and dihydroxylation. Cloniprazepam was metabolized to numerous metabolites with the main metabolic steps being N-dealkylation, hydroxylation and reduction of the nitro function. It has to be noted that clonazepam is a metabolite of cloniprazepam, which may lead to difficulties when interpreting analytical findings. Nitrazolam and fonazepam both underwent monohydroxylation and reduction of the nitro function. In the case of 3-OH-phenazepam, no in vitro phase I metabolites were detected. Formation of licensed benzodiazepines (clonazepam after uptake of cloniprazepam) and the sale of metabolites of prescribed benzodiazepines (fonazepam, identical to norflunitrazepam, and 3-hydroxyphenazepam) present the risk of incorrect interpretation of analytical findings. Copyright © 2016 John Wiley & Sons, Ltd.

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“…Thus, most available reports on the chronic administration of benzodiazepines suggest that these compounds are not tumorigenic. Perhaps this failure to induce hepatic cell or other neoplasms is related to the extensive biotransformation of the compounds by hepatocytes ' (Viau et al, 1972(Viau et al, , 1973. We have investigated the possibility that these tumors be the result of direct genotoxic insult, and ripazepam did not induce revertants in the standard bacterial plate assay with five strains of Salmonella typhimurium (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

Carcinogenicity studies in rodents with ripazepam, a minor tranquilizing agent

Fitzgerald

1984

Fundamental and Applied Toxicology

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The carcinogenesis potential of ripazepam , a benzodiazepine derivative, was studied in mice and rats for 78 and 104 weeks, respectively. Groups of 50 male and 50 female CD1 mice and CD rats each were given doses of 15 and 150 mg/kg of ripazepam in the diet. Survival rates were adequate for statistical analysis. Significant suppression of body weight gains occurred in rats but not in mice given 150 mg/kg/day. The compound failed to increase tumor rates or alter the average latency of neoplasm in the rat, the number of male animals with tumors was increased at 150 mg/kg and this was related to a significant increase in the number of animals with hepatocellular tumors. Hepatocellular tumors were increased also in female mice but the increase was not statistically significant. All but one of these hepatic neoplasms were hepatocellular adenomas and the one carcinoma had not metastasized. Other tumor types were not increased.

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Prazepam Metabolism in the Rat

Cited by 9 publications

References 16 publications

Concentrations of N‐descyclopropyl‐methylprazepam in whole‐blood, plasma, and milk after administration of prazepam to humans

Concentrations of N‐descyclopropyl‐methylprazepam in whole‐blood, plasma, and milk after administration of prazepam to humans

Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines — an update comprising adinazolam, cloniprazepam, fonazepam, 3‐hydroxyphenazepam, metizolam and nitrazolam

Carcinogenicity studies in rodents with ripazepam, a minor tranquilizing agent

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