Brain endothelial permeability, transport, and flow assessed over 10 orders of magnitude using the in situ brain perfusion technique.

Background: Cerebral blood flow normally places a limit on the magnitude of brain vascular permeability (P) that can be measured in vivo. At normal cerebral blood flow, this limit falls at the lower end of lipophilicity for most FDA-approved CNS drugs. In this study, we report on two methods that can be used to overcome this limitation and measure brain vascular permeability values that are up to ~1000 times higher using the in situ brain perfusion technique.

Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats.

Objectives: The recommended zolpidem starting dose was lowered in females (5 mg vs. 10 mg) since side effects were more frequent and severe than those of males; the mechanism underlying sex differences in pharmacokinetics (PK) is unknown. We hypothesized that such differences were caused by known sex-related variability in alcohol dehydrogenase (ADH) expression.

Brain uptake, pharmacokinetics, and tissue distribution in the rat of neurotoxic N-butylbenzenesulfonamide.

The pharmacokinetics, cerebrovascular permeability, and tissue distribution of the neurotoxic plasticizer N-butylbenzenesulfonamide (NBBS) were determined in rats. A stable isotope-labeled form ([(13)C(6)]NBBS) was used to circumvent ubiquitous contamination that was evident whenever the native form was measured. Plasticizer decline in plasma, following an iv dose of 1 mg/kg, was described by a triexponential decay function.

Brain uptake of nonsteroidal anti-inflammatory drugs: ibuprofen, flurbiprofen, and indomethacin.

Purpose: To determine the roles of blood-brain barrier (BBB) transport and plasma protein binding in brain uptake of nonsteroidal anti-inflammatory drugs (NSAIDs)-ibuprofen, flurbiprofen, and indomethacin.

Methods: Brain uptake was measured using in situ rat brain perfusion technique.

Results: [14C]Ibuprofen, [3H]flurbiprofen, and [14C]indomethacin were rapidly taken up into the brain in the absence of plasma protein with BBB permeability-surface area products (PS(u)) to free drug of (2.

Role of site-specific binding to plasma albumin in drug availability to brain.

Many studies have reported greater drug uptake into brain than that predicted based upon existing models using the free fraction (f(u)) of drug in arterial serum. To explain this difference, circulating plasma proteins have been suggested to interact with capillary membrane in vivo to produce a conformational change that favors net drug dissociation and elevation of f(u). Albumin, the principal binding protein in plasma, has two main drug binding sites, Sudlow I and II.