Biliary Excretion of Conjugated Hydroxyl Benzodiazepines after Administration of Several Benzodiazepines to Rats, Guinea Pigs, and Mice

Bertagni, P; Marcucci, F.; Mussini, E.; Garattini, Silvio

doi:10.1002/jps.2600610635

Cited by 21 publications

(9 citation statements)

References 12 publications

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“…However, the data of Tognoni et al (1975) show a consistent rise in plasma concentration from 10 h to 12 h after the drug. This, for reasons given above, is unlikely to reflect continued primary absorption but has been postulated to relate to an extensive enterohepatic circulation (Bertagni, Marcucci, Mussini & Garattini, 1972). In another study, the mean 'steady-state' plasma concentration after 20 mg/day was 884 ng/ml, consistent with our mean levels on 15 mg/day (Post, Lindgren, Bertler & Malingren, 1977).…”

Section: Discussionsupporting

confidence: 84%

Physiological and psychological effects of clorazepate in man.

Lader¹,

Curry²,

Baker³

1980

Brit J Clinical Pharma

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1 In the first study, eight healthy volunteers were-given single oral doses of 5, 7.5 and 15 mg clorazepate dipotassium (Tranxene), a precursor of N-desmethyldiazepam, and placebo. Drug effects up to 5 h after administration were assessed on a battery of physiological, psychomotor and subjective tests. 2 Psychotropic effects were not marked but decreases in EEG auditory responses and increases in EEG fast-wave activity were detected. Some psychomotor impairment was apparent after the 15 mg dose. Subjective effects comprised some lowering of alertness and changes in sociability. Plasma concentrations of N-desmethyldiazepam 3 h after ingestion were related to dose and correlations were found with the other variables. 3 In the second study, nine subjects received clorazepate 7.5 and 15 mg, and placebo, in a single daily dose for 14 days, with at least 5 weeks between courses. Psychotropic effects were evaluated on the first and last days of drug administration, for up to 5 h following the daily dose. After 15 days, EEG auditory responses were diminished and fast-wave activity increased. Anxiety was diminished but psychomotor effects were minimal. 4 Psychotropic effects following the dose of clorazepate dipotassium on day 15 were compared with those on day 1. Objective measures, the EEG auditory response, fast-wave activity and critical flicker fusion, were significantly less affected on day 15 than on day 1 whereas subjective ratings and the digit-symbol substitution test were more affected. 5 Plasma concentrations of N-desmethyldiazepam increased in a dose-related way over the 2 weeks. Increases following the drug on day 15 were at least as large as those on day 1 suggesting that pharmacokinetic factors could not account for the physiological tolerance noted above. 6 It was concluded that clorazepate dipotassium in doses of 7.5 mg/day provided useful anxiolytic actions without undue sedation.

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Section: Discussionsupporting

confidence: 84%

Physiological and psychological effects of clorazepate in man.

Lader¹,

Curry²,

Baker³

1980

Brit J Clinical Pharma

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“…However, the data by Inaba et al, (13), Bertagni et aI. (12), Sellman et at. (14,15) and the present study suggest, that this route of elimination is neglegible for diazepam, pinazepam, and their unconjugate metabolites, at least in the rats and humans.…”

Section: Discussioncontrasting

confidence: 41%

“…The enterohepatic circulation of a drug can influence its plasmatic decay (II). Very little is known on the biliary excretion of benzodiazepines (12,13,14,15) and no data were available for pinazepam.…”

mentioning

confidence: 99%

Disposition, distribution, plasma protein bindingand biliary excretion of pinazepam after i.p. administration to rat

Pacifici

Cuoci

Placidi

1983

European Journal of Drug Metabolism and Pharmacokinetics

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The pharmacokinetics, distribution, plasma protein binding and the biliary excretion of pinazepam were studied in the rat. The drug was administered (5 mg/kg) by i.p. injection. The chemical analysis of pinazepam and its metabolites was carried out by a gas-chromatographic method. The parent compound was rapidly absorbed, accumulated into the tissues and converted into N-desmethyldiazepam. The highest plasma levels of the parent compound (367 +/- 13 ng/ml) were found 3 min after administration. The volume of distribution and the clearance of the drug were 1315 ml and 7.23 ml/min respectively. The metabolite was detected in the plasma and tissues 3 min after administration. At this sampling time its concentrations were 76 +/- 16 ng/ml in the plasma and 1081 +/- 68 ng/g in the liver. The decay curve of both pinazepam and N-desmethyldiazepam in the plasma, liver, lung, heart, kidney, brain, and gastrochemius muscle were characterized for their Kel, t 1/2, and AUC values. The tissue AUC to plasma AUC ratios indicated a preferential accumulation of pinazepam over its metabolite in the tissues. The plasma protein binding of pinazepam was measured by dialysis at the equilibrium. Rat plasma proteins bound 89.17 +/- 0.20 percent of the drug. The association constant was 2.60 X 10(3) l/mole and the number of sites 0.44 X 10(-6) sites/g. The biliary excretion of pinazepam and N-desmethyldiazepam was poor.

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“…Tissue depots as sites of the accumulation of diazepam and its metabolites have been studied intensively (MARCUCCI et al 1968(MARCUCCI et al & 1970 VAN ERKKOLA et al 1974;KANTO et al 1974c;SERENI 1974), but the enterohepatic circulation has been largely overlooked. In an animal study species variations in the capacity to excrete diazepam and its metabolites into the bile have been found (BERTAGNI et al 1972). To our knowledge, concentrations in the human bile have never been measured before.…”

mentioning

confidence: 94%

Biliary Excretion of Diazepam and its Metabolites in Man

Sellman

Kanto

Pekkarinen

1975

Acta Pharmacologica et Toxicologica

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Abstmct: Ten mg diazepam was given intravenously to 12 patients with a T-tube in the common bile duct after choledochotomy (Group I) and to 10 patients after cholecystectomy (Group 11). The concentrations of diazepam, of its main metabolite, N-demethyldiazepam, and of free oxazepam in the plasma of both groups and the conjugated and free concentrations of diazepam, N-demethyldiazepam, and oxazepam in the bile in the Group I were measured by gas chromatography. In Group I significantly lower plasma diazepam concentrations were obtained as compared with Group I1 indicating an enterohepatic circulation of diazepam. There was no significant difference in the concentrations of Ndemethyldiazepam in the plasma between the two groups. In Group I the patients had frequently more free oxazepam in their plasma than in Group 11. The main conjugated metabolite in the bile was N-demethyldiazepam (about 74 %). Traces of diazepam were in the conjugated form, but no conjugated oxazepam was found in the human bile. The enterohepatic circulation of diazepam and its metabolites may be partly responsible for the prolonged effects of diazepam.

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Biliary Excretion of Conjugated Hydroxyl Benzodiazepines after Administration of Several Benzodiazepines to Rats, Guinea Pigs, and Mice

Cited by 21 publications

References 12 publications

Physiological and psychological effects of clorazepate in man.

Physiological and psychological effects of clorazepate in man.

Disposition, distribution, plasma protein bindingand biliary excretion of pinazepam after i.p. administration to rat

Biliary Excretion of Diazepam and its Metabolites in Man

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