Diazepam and N‐desmethyldiazepam concentrations in saliva, plasma and CSF.

Abstract

1 Salivary and plasma diazepam and nordiazepam concentrations were measured in 51 paired samples from four experimental situations. In seven of the patients CSF samples were estimated. 2 Correlation of 0.89 (P less than 0.001) was observed between salivary and plasma diazepam and 0.81 (P less than 0.001) between salivary and plasma nordiazepam. 3 Mean salivary diazepam was 1.6% (+/‐ 0.3%) of the plasma diazepam. It was found to vary markedly in an acute dosage study. Mean salivary nordiazepam was 2.9% (+/‐ 1%) of the plasma measure and was dependent on salivary flow rate. 4 CSF diazepam was in equilibrium with unbound plasma diazepam and salivary diazepam. 5 Mean protein binding of diazepam in vitro was 99.3% with no variations as a function of concentration. 6 The results suggest salivary diazepam and nordiazepam measures to be of value in epidemiological studies. However, they do not predict accurately the plasma total or unbound drug concentration from a salivary sample in an individual.

Inhibition of Recombinant L-Type Voltage-Gated Calcium Channels by Positive Allosteric Modulators of GABAA Receptors

“…Free plasma and cerebrospinal fluid concentrations of BDZs, barbiturates, and ethanol exist in an approximate 1:1 ratio (Richards, 1972;Hallstrom and Lader, 1980;Harris et al, 2008). Taking into account extensive binding (Ͼ97%) of diazepam and its active metabolite, desmethyldiazepam, to plasma proteins (Hallstrom and Lader, 1980;Divoll and Greenblatt, 1981), free plasma concentrations of approximately 20 to 60 nM are necessary for acute relief of convulsant activity (Rey et al, 1999), and approximately 50 to 100 nM is needed to produce sedation (Lundgren, 1987).…”

“…Taking into account extensive binding (Ͼ97%) of diazepam and its active metabolite, desmethyldiazepam, to plasma proteins (Hallstrom and Lader, 1980;Divoll and Greenblatt, 1981), free plasma concentrations of approximately 20 to 60 nM are necessary for acute relief of convulsant activity (Rey et al, 1999), and approximately 50 to 100 nM is needed to produce sedation (Lundgren, 1987). Because of rapid tolerance to the sedative effects of diazepam, higher concentrations up to 200 nM are achieved during long-term treatment for psychiatric therapy (Rutherford et al, 1978;Hallstrom and Lader, 1980;Greenblatt et al, 1981). Because the threshold concentration of BDZs to significantly inhibit recombinant L-VGCCs was approximately 10 M, inhibition of neuronal L-VGCCs is unlikely to contribute to BDZ clinical actions.…”

Statistical learning approach for predicting specific pharmacodynamic, pharmacokinetic, or toxicological properties of pharmaceutical agents

“…For instance, a drug with high BB ratio may not have effects in the brain either because of the absence of target receptors or insufficient potencies towards the target receptors in the brain. Conversely, a drug with a relatively low BB ratio may still have effects in the brain because of its high potency towards specific receptors [Hallstrom and Lader, 1980]. Such correlations, which have not been adequately considered in statistical learning methods so far, may need to be incorporated in developing statistical learning models for predicting those pharmacokinetic properties that are known to correlate with a certain pharmacodynamic property.…”

Relationships Between CSF Drug Concentrations, Receptor Binding Characteristics, and Pharmacokinetic and Pharmacodynamic Properties of Selected 1,4-Substituted Benzodiazepines

“…Both human and animal studies with diazepam, desmethyldiazepam, chlordiazepoxide and clonazepam have shown that eSF concentrations are equivalent to the free drug concentrations in blood following distribution (Greenblatt et aI. 1980;Halstrom et al 1980;Hendel 1975;Kanto et al 1975;Parry 1977;Stanski et al 1976). These observations suggest that protein binding regulates the amount of drug available to cross the blood-brain barrier, with the affinity for the receptor regulating the potency and duration of the pharmacological activity.…”