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Brain Penetration (brain + penetration)
Selected AbstractsBlood,brain barrier damage and brain penetration of antiepileptic drugs: Role of serum proteins and brain edemaEPILEPSIA, Issue 4 2009Nicola Marchi Summary Purpose:, Increased blood,brain barrier (BBB) permeability is radiologically detectable in regions affected by drug-resistant epileptogenic lesions. Brain penetration of antiepileptic drugs (AEDs) may be affected by BBB damage. We studied the effects of BBB damage on brain distribution of hydrophilic [deoxy-glucose (DOG) and sucrose] and lipophilic (phenytoin and diazepam) molecules. We tested the hypothesis that lipophilic and hydrophilic drug distribution is differentially affected by BBB damage. Methods:, In vivo BBB disruption (BBBD) was performed in rats by intracarotid injection of hyperosmotic mannitol. Drugs (H3-sucrose, 3H-deoxy-glucose, 14C-phenytoin, and C14-diazepam) or unlabeled phenytoin was measured and correlated to brain water content and protein extravasation. In vitro hippocampal slices were exposed to different osmolarities; drug penetration and water content were assessed by analytic and densitometric methods, respectively. Results:, BBBD resulted in extravasation of serum protein and radiolabeled drugs, but was associated with no significant change in brain water. Large shifts in water content in brain slices in vitro caused a small effect on drug penetration. In both cases, total drug permeability increase was greater for lipophilic than hydrophilic compounds. BBBD reduced the amount of free phenytoin in the brain. Discussion:, After BBBD, drug binding to protein is the main controller of total brain drug accumulation. Osmotic BBBD increased serum protein extravasation and reduced free phenytoin brain levels. These results underlie the importance of brain environment and BBB integrity in determining drug distribution to the brain. If confirmed in drug-resistant models, these mechanisms could contribute to drug brain distribution in refractory epilepsies. [source] Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humansFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2004M. Molimard Abstract Absorption, distribution, metabolism and excretion of desloratadine, fexofenadine, levocetirizine, and mizolastine in humans have been compared. The time required to reach peak plasma levels (tmax) is shortest for levocetirizine (0.9 h) and longest for desloratadine (,3 h). Steady-state plasma levels are attained after about 6 days for desloratadine, 3 days for fexofenadine, 2,3 days for mizolastine and by the second day for levocetirizine. The apparent volume of distribution is limited for levocetirizine (0.4 L/kg) and mizolastine (1,1.2 L/kg), larger for fexofenadine (5.4,5.8 L/kg) and particularly large for desloratadine (, 49 l/kg). Fexofenadine and levocetirizine appear to be very poorly metabolized (, 5 and 14% of the total oral dose, respectively). Desloratadine and mizolastine are extensively metabolized. After administration of 14C-levocetirizine to healthy volunteers, 85 and 13% of the radioactivity are recovered in urine and faeces, respectively. In contrast, faeces are the preferential route of excretion for 14C-fexofenadine (80% vs. 11% of the radioactive dose in urine). The corresponding values are 41% (urine) and 47% (faeces) for 14C-desloratadine, 84,95% (faeces) and 8,15% (urine) for 14C-mizolastine. The absolute bioavailability is 50,65% for mizolastine; it is high for levocetirizine as the percentage of the drug eliminated unchanged in the 48 h urine is 77% of the oral dose; the estimation for fexofenadine is at least 33%; no estimation was found for desloratadine. Fexofenadine is a P-glycoprotein (P-gp) substrate and P-gp is certainly involved both in the poor brain penetration by the compound and, at least partially, in a number of observed drug interactions. An interaction of desloratadine with P-gp has been suggested in mice, whereas the information on mizolastine is very poor. The fact that levocetirizine is a substrate of P-gp, although weak in an in vitro model, could contribute to prevent drug penetration into the brain, whereas it is unlikely to be of any clinical relevance for P-gp-mediated drug interactions. [source] Effect of dose and input rate on the brain penetration of BMS-204352 following intravenous administration to ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2002Rajesh Krishna Abstract BMS-204352 is a novel maxi-K channel opener that is being developed for the treatment for stroke. The current study was designed to evaluate the plasma and brain pharmacokinetics of BMS-204352 in rats, in particular, assessing the effect of dose and input rate on brain penetration of BMS-204352. Rats (3 animals/group/time point) received a single intravenous dose of BMS-204352 as 5 mg/kg bolus, 5 mg/kg 30 min infusion, 5 mg/kg 60 min infusion, and 10 mg/kg bolus dose, into the jugular vein. Terminal blood (for plasma) and brain samples were collected for up to 9 h post-dose and samples were analyzed for the concentrations of intact BMS-204352 using a validated liquid chromatographic tandem mass spectrometric method (LC/MS/MS). As dose increased from 5 to 10 mg/kg, both BMS-204352 Cmax and AUC values increased in plasma and brain, somewhat greater in proportion to the increment in dose. Whereas the peak concentrations of BMS-204352 were affected by infusion time, overall AUCs were comparable across the bolus and infusion groups. Terminal disposition (T -half ranged from 1.6 to 2.7 h) of BMS-204352 was unaltered as a function of input rate. BMS-204352 crossed the blood,brain barrier with brain-to-plasma (B/P) ratios of approximately 7,11. Brain-to-plasma ratios appeared to be independent of dose and infusions produced somewhat higher brain penetration (B/P of ca. 11) as compared to bolus (B/P of ca. 7,8) dose. The decline of BMS-204352 in the brain paralleled that of plasma independent of the input rate and dose. Copyright © 2002 John Wiley & Sons, Ltd. [source] Anticonvulsant activity, teratogenicity and pharmacokinetics of novel valproyltaurinamide derivatives in miceBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2003Nina Isoherranen The purpose of this study was to synthesize novel valproyltaurine (VTA) derivatives including valproyltaurinamide (VTD), N -methyl-valproyltaurinamide (M-VTD), N,N -dimethyl-valproyltaurinamide (DM-VTD) and N -isopropyl-valproyltaurinamide (I-VTD) and evaluate their structure,pharmacokinetic,pharmacodynamic relationships with respect to anticonvulsant activity and teratogenic potential. However, their hepatotoxic potential could not be evaluated. The metabolism and pharmacokinetics of these derivatives in mice were also studied. VTA lacked anticonvulsant activity, but VTD, DM-VTD and I-VTD possessed anticonvulsant activity in the Frings audiogenic seizure susceptible mice (ED50 values of 52, 134 and 126 mg kg,1, respectively). VTA did not have any adverse effect on the reproductive outcome in the Swiss Vancouver/Fnn mice following a single i.p. injection of 600 mg kg,1 on gestational day (GD) 8.5. VTD (600 mg kg,1 at GD 8.5) produced an increase in embryolethality, but unlike valproic acid, it did not induce congenital malformations. DM-VTD and I-VTD (600 mg kg,1 at GD 8.5) produced a significant increase in the incidence of gross malformations. The incidence of birth defects increased when the length of the alkyl substituent or the degree of N -alkylation increased. In mice, N-alkylated VTDs underwent metabolic N-dealkylation to VTD. DM-VTD was first biotransformed to M-VTD and subsequently to VTD. I-VTD's fraction metabolized to VTD was 29%. The observed metabolic pathways suggest that active metabolites may contribute to the anticonvulsant activity of the N-alkylated VTDs and reactive intermediates may be formed during their metabolism. In mice, VTD had five to 10 times lower clearance (CL), and three times longer half-life than I-VTD and DM-VTD, making it a more attractive compound than DM-VTD and I-VTD for further development. VTD's extent of brain penetration was only half that observed for the N-alkylated taurinamides suggesting that it has a higher intrinsic activity that DM-VTD and I-VTD. In conclusion, from this series of compounds, although VTD caused embryolethality, this compound emerged as the most promising new antiepileptic drug, having a preclinical spectrum characterized by the highest anticonvulsant potential, lowest potential for teratogenicity and favorable pharmacokinetics. British Journal of Pharmacology (2003) 139, 755,764. doi:10.1038/sj.bjp.0705301 [source] Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New ConceptCHEMISTRY & BIODIVERSITY, Issue 11 2009Andreas Reichel Abstract Despite enormous efforts, achieving a safe and efficacious concentration profile in the brain remains one of the big challenges in central nervous system (CNS) drug discovery and development. Although there are multiple reasons, many failures are due to underestimating the complexity of the brain, also in terms of pharmacokinetics (PK). To this day, PK support of CNS drug discovery heavily relies on improving the blood,brain barrier (BBB) permeability in vitro and/or the brain/plasma ratio (Kp) in vivo, even though neither parameter can be reliably linked to pharmacodynamic (PD) and efficacy readouts. While increasing BBB permeability may shorten the onset of drug action, an increase in the total amount in brain may not necessarily increase the relevant drug concentration at the pharmacological target. Since the traditional Kp ratio is based on a crude homogenization of brain tissue, it ignores the compartmentalization of the brain and an increase favors non-specific binding to brain lipids rather than free drug levels. To better link exposure/PK to efficacy/PD and to delineate key parameters, an integrated approach to CNS drug discovery is emerging which distinguishes total from unbound brain concentrations. As the complex nature of the brain requires different compartments to be considered when trying to understand and improve new compounds, several complementary parameters need to be measured in vitro and in vivo, and integrated into a coherent model of brain penetration and distribution. The new paradigm thus concentrates on finding drug candidates with the right balance between free fraction in plasma and brain, and between rate and extent of CNS penetration. Integrating this data into a coherent model of CNS distribution which can be linked to efficacy will allow it to design compounds with an optimal mix in physicochemical, pharmacologic, and pharmacokinetic properties, ultimately mitigating the risk for failures in the clinic. [source] Optimized Synthesis of AMPA Receptor Antagonist ZK,187638 and Neurobehavioral Activity in a Mouse Model of Neuronal Ceroid LipofuscinosisCHEMMEDCHEM, Issue 10 2006Bernd Elger Dr. Abstract Previous structure,activity relationship studies in the search for a potent, noncompetitive , -amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist led to 2,3-dimethyl-6-phenyl-12H -[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine (ZK,187638). However, the first synthesis had some drawbacks regarding reagents, processes, and overall yield, which furthermore decreased when the synthesis was scaled up. Therefore, we now report a new synthetic route for this compound which requires fewer steps and is suited for large-scale production. This compound significantly relieved the symptoms of neuromuscular deficit in mnd mice, a model of neuronal ceroid lipofuscinosis with motor neuron dysfunction. After oral administration, the concentrations of the compound in the brain and spinal cord were about threefold higher than those in the plasma. In summary, this novel AMPA antagonist is accessible through an optimized synthetic route, has good neurobehavioral activity, oral bioavailability, and favorable brain penetration. This opens new possibilities for the treatment of devastating neurological diseases that are mediated by the AMPA receptor. [source] | |||||||||||||