Further studies on species difference in diazepam metabolism

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

doi:10.1016/0014-2999(70)90308-0

Cited by 49 publications

(12 citation statements)

References 5 publications

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“…Kvetina et al [10] reported that temazepam can, to some extent, be recognized in perfused fluid of rat liver, but Marducci et al [11] showed that temazepam is not found as a metabolite of diazepam in blood, indicating that the amount of temazepam is negligible in blood and brain of rats. These reports show that the benzodiazepine derivative determined in this study was not temazepam but almost certainly diazepam, although the cross-reactivity of [4] Diazepam in rat serum could be detected within 30 min after administration and its half-life was approximately 1 h (Fig.…”

Section: Discussionmentioning

confidence: 98%

A comparative study of diazepam levels in bone marrow versus serum, saliva and brain tissue

et al. 1991

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The distribution of diazepam in biological fluids and tissues of rats was examined 1, 2, 4 and 8 h after intraperitoneal administration by using a radioimmunoassay with specific anti-diazepam antibody. The diazepam levels in serum, saliva, brain and bone marrow decreased over a period of 2 h and levelled off 4 h after administration. The diazepam concentration in bone marrow was much higher than in serum, saliva and brain, suggesting an accumulation of diazepam in this tissue. This indicates that bone marrow could be a very useful material for the detection of diazepam in skeletonized remains. The diazepam concentrations in bone marrow, serum, saliva and brain showed a linear relationship (r = 0.860-0.997), indicating that a valid estimate of diazepam concentration in blood can be made from bone marrow samples.

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Section: Discussionmentioning

confidence: 98%

A comparative study of diazepam levels in bone marrow versus serum, saliva and brain tissue

et al. 1991

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“…Quantitative measurement of these compounds using a specific and sensitive analysis has only relatively recently become possible (Belvedere et al, 1972). The formation of these metabolites after administration in man does not seem to have any clinical relevance, although in certain animal species they explain the long duration of action of diazepam (Marcucci et al, 1968b;Marcucci et al, 1970). The overall consideration of data presented up to this point seems to allow a practical suggestion, the validity and efficacy of which could be checked in clinical practice.…”

Section: Plasma Level Profile and Elimination Kineticsmentioning

confidence: 98%

Clinical Pharmacokinetics of Diazepam

Mandelli

Tognoni

Garattini

1978

Clinical Pharmacokinetics

442

107

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Diazepam is still one of the most used of the benzodiazepine group of drugs. Extensive studies over 10 years have defined a fairly complete profile of its kinetics. Minor aspects relating to patterns of its metabolism and excretion in certain age groups and in some disease states remain to be described quantitatively. However, there is more than sufficient kinetic information available for the requirements of good clinical practice. For optimum clinical benefit with minimum side-effects the following kinetic properties should be borne in mind: (a) there is a large interindividual variation (up to 30-fold) in dose/blood level ratios, especially when treatment is short-term; (b) the elimination half-life is prolonged in the elderly and the newborn and in some cases of liver disease; (c) there is accumulation of the active N-desmethylated metabolite during long-term treatment; and (d) administration of diazepam to pregnant women leads to rapid distribution from the maternal to fetal compartment: accumulation of both diazepam and desmethyldiazepam could cause prolonged sedation in the newborn. As there does not appear to be any clear relationship between the concentration of diazepam in the plasma and clinical effect, measurement of blood levels, other than for research purposes, is unnecessary. Based on kinetic data, a single administration of diazepam at night should be adequate for hypnotic and anxiolytic effects in most patients.

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“…After recovery from acute viral hepatitis, the diazepam half-life returned almost to normal values; No statistically significant correlation was noted between the diazepam ti (a) in patients with cirrhosis or hepatitis (and drug clearance in cirrhosis) and any of the standard liver function tests. The reduced clearance of diazepam in patients with acute and chronic parenchymal liver disease suggests that this drug should be used with caution, especially on a prolonged basis, in (1)(2)(3)(4)(5). In man, the major biotransformation pathways include demethylation to Ni-desmethyldiazepam, the major metabolite detectable in the plasma, and, to a lesser extent, hydroxylation to form Ni-methyloxazepam.…”

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confidence: 99%

“…These two metabolites are hydroxylated and N-demethylated, respectively, to form oxazepam. The hydroxylated metabolites are then conjugated to their respective glucuronides, with oxazepam glucuronide as the major urinary product (1)(2)(3)(4)(5). Most studies of the plasma elimination of diazepam have been limited to data obtained after oral administration of the drug, particularly after prolonged therapy.…”

mentioning

confidence: 99%