Effect of phenobarbital on the in vitro metabolism of diazepam in several animal species

Marcucci, F.; Fanelli, Roberto; Mussini, E.; Garattini, Silvio

doi:10.1016/0006-2952(70)90169-3

Cited by 19 publications

(10 citation statements)

References 6 publications

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“…Marucci et al (1970) demonstrated an increase in the rate of diazepam metabolism in rats, mice and guinea pigs treated with phenobarbitone. Ohnhaus et al (1979) showed that the metabolism of diazepam in man was increased following the induction of liver microsomal enzymes by antipyrine.…”

Section: Introductionmentioning

confidence: 99%

Single dose pharmacokinetic study of clobazam in normal volunteers and epileptic patients.

Jawad¹,

Richens²,

Oxley³

1984

Brit J Clinical Pharma

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1 The pharmacokinetics of clobazam were studied in six healthy volunteers and six age and sex matched enzyme-induced epileptic patients. 2 In the epileptic patients the area under the plasma concentration-time curve for clobazam was significantly smaller and the area under the plasma concentration-time curve for N-desmethylclobazam was significantly greater than in the healthy volunteers. 3 Plasma N-desmethylclobazam concentrations were found to be much higher than those of clobazam in the epileptic patients, raising the possibility that the antiepileptic properties of clobazam are to be attributed more to its metabolite than the parent drug.

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Section: Introductionmentioning

confidence: 99%

Single dose pharmacokinetic study of clobazam in normal volunteers and epileptic patients.

Jawad¹,

Richens²,

Oxley³

1984

Brit J Clinical Pharma

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“…In experiments in animals similar results were found following chronic phenobarbitone administration whereby both N-demethylation and hydroxylation to oxazepam were increased in rats. In contrast, in mice and guinea pigs only one metabolic pathway either hydroxylation or N-demethylation was influenced by phenobarbitone administration (Marucci et al, 1970).…”

Section: Discussionmentioning

confidence: 79%

“…Therefore, the influence of other drugs known as enzyme inducing agents in man on diazepam elimination and possible induction of different metabolic pathways of diazepam metabolism as found in the animal experiments (Marucci et al,, 1970) has to be further elucidated. However, based on the increased elimination of diazepam and desmethyldiazepam found in the present study a decreased pharmacodynamic effect seems possible in induced individuals, which might be sometimes of clinical importance.…”

Section: Discussionmentioning

confidence: 99%

“…In experiments in animals it was found that diazepam given in daily doses of 400 mg/kg bodyweight to rats stimulated hepatic microsomal metabolism as evidenced by acceleration of both p-hydroxylation of aniline and hydroxylation of benzene (Jablonska, Knobloch, Majka & Wisniewska-Knypl, 1975). In addition, rats, mice and guinea pigs treated with phenobarbitone showed an increase in diazepam metabolism affecting the different metabolites known in the degradation of diazepam elimination (Marucci, Fanelli, Mussini & Garattini, 1970 0306-5251/79/110557-07 $01.00 patients on long term diazepam therapy (Sellman, Kanto, Raijolo & Pekkarinen, 1975). However, the effect on diazepam metabolism of other drugs like antipyrine and phenobarbitone known to be enzyme inducers in man has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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The effect of enzyme induction on diazepam metabolism in man.

Ohnhaus¹,

Park²,

Colombo³

et al. 1979

Brit J Clinical Pharma

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1 The elimination and metabolism of diazepam in man was investigated following the induction of the liver microsomal enzyme system by antipyrine. 2 Seven healthy volunteers were given 1200 mg antipyrine as an inducing agent for a period of 14 days. Before and after the induction period the elimination of diazepam and desmethyldiazepam was measured in the plasma by gaschromatography. As parameters of liver microsomal enzyme activity, antipyrine elimination and gamma‐glutamyl‐ transpeptidase in the plasma, D‐glucaric acid and 6‐beta‐ hydroxycortisol urinary excretion were measured on both occasions. 3 Following the induction period most parameters of microsomal enzyme activity measured were significantly changed indicating an increase of the microsomal enzyme system. The elimination of diazepam was significantly altered having a half‐life of 37 h before and 18 h afterwards combined with a significant increase in total body clearance after the induction period, although the volume of distribution remained unaltered. The formation of the main metabolite N‐ desmethyldiazepam was not changed, but its elimination was increased having a half‐life of 139 or 58 h respectively. 4 The elimination of unchanged diazepam and desmethyldiazepam is significantly increased by the induction of the liver microsomal enzyme system using antipyrine as an inducing agent in healthy volunteers, which might be important under certain clinical conditions.

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“…The presence of the hydroxylated metabolites in the brain of mice, but not of rats (14), explains the long duration of the effect exerted by I and 111 in mice but not in rats (12). The facts that both I and I11 are equally hydroxylated in uitro by the liver microsomes of rats and mice but that the hydroxylated metabolites accumulate only in the brain of mice may be due to a rapid metabolism of hydroxylated benzodiazepines in rats (15,16).…”

Section: Resultsmentioning

confidence: 98%