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

Abstract

Pharmacokinetic profiles of the 1,4-substituted benzodiazepines are defined by their absorption, distribution, metabolism, and excretion characteristics. An ability to cross the blood-brain barrier and the onset of pharmacological activity have been associated with the physiochemical properties of the benzodiazepines. In addition, drug concentrations in the CSF correlate with the unbound drug concentrations in blood or plasma. Duration of pharmacological activity of the benzodiazepines in humans is associated with the affinity of these compounds for the benzodiazepine receptors in human brain. Therefore, benzodiazepines with high affinity for the benzodiazepine receptor sites in human brain tend to exhibit prolonged half-lives of elimination from the CSF which correlate with the prolonged duration of clinical and pharmacological effects and lower therapeutic doses of these drugs in vivo.

Orally Active Isoxazoline Glycoprotein IIb/IIIa Antagonists with Extended Duration of Action

“…[20][21][22]27,37 Affinity for unactivated GPIIb/ IIIa receptors and resting platelets has been proposed as a mechanism to decrease clearance and prolong antiplatelet effects of GPIIb/IIIa antagonists. 27,38,39 Analogous target-mediated clearance of ACE inhibitors from plasma 40 and of benzodiazepines from cerebrospinal fluid 41 has been reported. The inhibition of aggregation in platelet-rich dog plasma, as well as the dissociation constants for activated and unactivated dog platelets, was measured for the stereoisomers of 34 (Table 5) (see Experimental Section).…”

“…The limitations of PRP aggregation assays include a sensitivity limited by the concentration of GPIIb/IIIa receptors in the assay mixture (∼20−40 nM), as well as the inability to distinguish the effects of protein binding from inherent GPIIb/IIIa affinity. Recently, certain GPIIb/IIIa antagonists having diaminopropionate carboxy-termini have been shown to possess considerable affinity for the unactivated platelet GPIIb/IIIa receptor, a further property not assessed by the PRP assay. − ,, Affinity for unactivated GPIIb/IIIa receptors and resting platelets has been proposed as a mechanism to decrease clearance and prolong antiplatelet effects of GPIIb/IIIa antagonists. ,, Analogous target-mediated clearance of ACE inhibitors from plasma and of benzodiazepines from cerebrospinal fluid has been reported. The inhibition of aggregation in platelet-rich dog plasma, as well as the dissociation constants for activated and unactivated dog platelets, was measured for the stereoisomers of 34 (Table ) (see Experimental Section).…”

Pharmacokinetic Optimisation of Antiemetic Therapy

“…Although the antiemetic effect is probably related to their sedative properties, considerable benefit is also derived from their anxiolytic and amnesic effects (Triozzi & Laszlo 1987). These effects are presumed to be mediated through benzodiazepine receptors in the brain and recent research has established that a cerebrospinal fluid (CSF) : plasma equilibrium exists and that pharmacodynamic effects and sedation correlate with brain concentrations (Colburn & Jack 1987;Greenblatt et al 1990). 155…”

Peripheral benzodiazepine receptors in platelets of epileptic patients.

“…These include a high affinity 'central' BZR (cBZR), which is linked to the gamma-aminobutyric acid (GABA) receptor/Cl-ionophore complex in the brain. Affinity to this receptor seems to correlate with the anticonvulsant and anxiolytic actions of many BZs [4,5]. More recently a 'peripheral' BZR (pBZR) has been identified.…”