Blood-brain barrier penetration and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcb1ab) knock-out mice and controls.

In earlier studies with P-gp (abcb1) knock-out mice, we showed that P-gp exports the antidepressants citalopram, paroxetine, venlafaxine and amitriptyline and its metabolites across the blood-brain barrier, thereby reducing cerebral bioavailability of some substances up to 9 times. The present study investigated the pharmacokinetics of amitriptyline and whether abcb1ab double knock-out mice metabolize amitriptyline and its metabolites differently. P-gp knock-out mice and controls received a s.

The anti-Parkinson drug budipine is exported actively out of the brain by P-glycoprotein in mice.

P-glycoprotein, a product of the ABCB1 gene, is a plasma membrane transporter that exports certain drugs as well as endogenous substances against a concentration gradient in the intestines, kidney and testes. It also constitutes an important part of the blood-brain barrier, where it exports its substrates out of the brain back into the circulation. To investigate whether the uptake of the anti-Parkinson drug budipine into the brain is mediated by P-glycoprotein, abcb1ab(-/-) double knock-out mice and wild-type control mice received budipine continuously over 11 days via implanted osmotic infusion pumps at the rate of 30ug over 24h.

P-glycoprotein is a factor in the uptake of dextromethorphan, but not of melperone, into the mouse brain: evidence for an overlap in substrate specificity between P-gp and CYP2D6.

In this study, the role of P-glycoprotein (P-gp) for the pharmacokinetics of dextromethorphan, a CYP2D6 substrate, and of melperone, a CYP2D6 inhibitor, was investigated. The substances were administered subcutaneously near the nape of the neck of wild-type mice and of abcb1ab (-/-) mice. One hour after injection, concentrations of the two drugs in cerebrum, plasma and in different organs were measured by high-performance liquid chromatography.

Influence of a long-term, high-dose volume therapy with 6% hydroxyethyl starch 130/0.4 or crystalloid solution on hemodynamics, rheology and hemostasis in patients with acute ischemic stroke. Results of a randomized, placebo-controlled, double-blind study.

Background: This study was performed to investigate the clinical effects of a 4-day volume therapy with a newly developed, 6% hydroxyethyl starch (HES) 130/0.4 versus crystalloid solution, with particular regard to systemic and cerebral hemodynamics, rheology and safety.

Methods: In a randomized, double-blind study, 40 patients suffering from an acute ischemic stroke received either 6% HES 130/0.

P-glycoprotein reduces the ability of amitriptyline metabolites to cross the blood brain barrier in mice after a 10-day administration of amitriptyline.

P-glycoprotein (P-gp) is a 170-kDa membrane protein and the gene product of the multiple drug resistance (MDR1 or ABCB1) gene. It constitutes an important part of the blood-brain barrier and actively exports a number of molecules across the blood-brain barrier back into the vascular space, subsequently reducing central nervous system (CNS) bioavailability of these substances. The aim of the present study was to investigate the pharmacokinetics of amitriptyline and its metabolites in P-gp (also called mdr1ab or abcb1ab) knockout mice and controls after a long-term adminstration for 10 days.

Treatment with anticoagulants in cerebral events (TRACE).

90 patients with acute stroke and a concomitant cardiac embolism source or a symptomatic high-grade stenosis of an extra-or intracranial vessel received in a mulitcenter, randomized, controlled study either Enoxaparin 1 mg/kg BW s.c. b.

Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption.

Background: Mice with a genetic disruption (knockout) of the multiple drug resistance (abcb1ab) gene were used to examine the effect of the absence of the drug-transporting P-glycoprotein (P-gp) at the blood-brain barrier on the uptake of the antidepressants venlafaxine, paroxetine, mirtazapine, and doxepin and its metabolites into the brain.

Methods: One hour after subcutaneous injection of venlafaxine, paroxetine, mirtazapine, or doxepin, knockout and wildtype mice were sacrificed, and the drug concentrations in brain, spleen, kidney, liver, and plasma were measured.

Results: The cerebrum concentrations of doxepin, venlafaxine, and paroxetine were higher in knockout mice, demonstrating that these substances are substrates of P-gp and that abcb1ab activity at the level of the blood-brain barrier reduces the penetration of these substances into the brain.

Influence of long-term volume therapy with hydroxyethyl starch on leukocytes in patients with acute stroke.

A repeated administration of hydroxyethyl starch affects hemostasiological and rheological factors such as the concentration of factor VIII/von Willebrand factor, platelet volume and plasma viscosity. An earlier study showed that HES also lowers the concentration of fibronectin, a molecule important in the reticuloendothelial system (RES). RES has a "clearing function" and is a part of the non-immune-specific defense mechanisms of the body.

abcb1ab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice.

The phenomenon of a heterogeneous response to the same drug in different patients is well-known. An important reason is that, even at equal concentrations, the bioavailability of a drug depends on the interaction of the drug with the blood-brain barrier (BBB). In part, this is due to the drug-transporting P-glycoprotein (P-gp), a product of the multiple drug resistance gene (ABCB1), which can transport drugs against a concentration gradient across the BBB back into the plasma and thereby reduce the bioavailability in the brain.