Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Fe d'errates disponible a: http://​dx.​doi.​org/​10.​1007/​s00213-013-3283-6Rationale Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine. Objective The major aims were to investigate the pharmacokineticsa and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model. Methods Mephedrone was administered to male Sprague-Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240 min. Results Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α=10.23 h−1, β=1.86 h−1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59±3.67%. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85±0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic-pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect. Conclusions We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude,and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity

Methamphetamine Inhibits the Glucose Uptake by Human Neurons and Astrocytes: Stabilization by Acetyl-L-Carnitine

Methamphetamine (METH), an addictive psycho-stimulant drug exerts euphoric effects on users and abusers. It is also known to cause cognitive impairment and neurotoxicity. Here, we hypothesized that METH exposure impairs the glucose uptake and metabolism in human neurons and astrocytes. Deprivation of glucose is expected to cause neurotoxicity and neuronal degeneration due to depletion of energy. We found that METH exposure inhibited the glucose uptake by neurons and astrocytes, in which neurons were more sensitive to METH than astrocytes in primary culture. Adaptability of these cells to fatty acid oxidation as an alternative source of energy during glucose limitation appeared to regulate this differential sensitivity. Decrease in neuronal glucose uptake by METH was associated with reduction of glucose transporter protein-3 (GLUT3). Surprisingly, METH exposure showed biphasic effects on astrocytic glucose uptake, in which 20 µM increased the uptake while 200 µM inhibited glucose uptake. Dual effects of METH on glucose uptake were paralleled to changes in the expression of astrocytic glucose transporter protein-1 (GLUT1). The adaptive nature of astrocyte to mitochondrial β-oxidation of fatty acid appeared to contribute the survival of astrocytes during METH-induced glucose deprivation. This differential adaptive nature of neurons and astrocytes also governed the differential sensitivity to the toxicity of METH in these brain cells. The effect of acetyl-L-carnitine for enhanced production of ATP from fatty oxidation in glucose-free culture condition validated the adaptive nature of neurons and astrocytes. These findings suggest that deprivation of glucose-derived energy may contribute to neurotoxicity of METH abusers

The influence of diazepam and midazolam on adenosine-induced forearm vasodilation in humans.

Contains fulltext : 59356.pdf (publisher's version ) (Closed access)Adenosine is an endogenous purine with vasodilating and cardioprotective properties. Animal experiments have shown that some benzodiazepine-induced effects can be explained by potentiation of adenosine effects, via inhibition of the nucleoside transport system. The objective of this study was to determine whether the frequently used benzodiazepines diazepam and midazolam increase adenosine-induced vasodilation in the human forearm vascular bed, measured by venous occlusion plethysmography. Adenosine (0.6, 6, 20, and 60 nmol/min/dl ForeArm Volume) was infused into the brachial artery with and without concomitant separate infusion of diazepam (21 nmol/min/dl, n = 9) and midazolam (23 nmol/min/dl, n = 8). Plasma concentrations of diazepam resp. midazolam at the end of the infusion protocol averaged 0.5 +/- 0.2 microg/ml plasma (1.6 microM) for diazepam versus 1.2 +/- 0.4 microg/ml plasma (3 microM) for midazolam. Intra-arterial infusion of the benzodiazepines did not alter baseline vascular tone, and had no significant influence on the forearm vasodilator response to adenosine. The adenosine-induced relative change in Forearm Vascular Resistance (FVR) was -3 +/- 7, -48 +/- 8, -75 +/- 6, and -85 +/- 3% in the absence and 3.5 +/- 11, -54 +/- 5, -74 +/- 5, and -82 +/- 3% resp. in the presence of diazepam (P > 0.1, repeated measures ANOVA, n = 9). Likewise, in the absence resp. presence of midazolam, FVR fell by 1 +/- 6, 55 +/- 5, 74 +/- 3, and 84 +/- 2% resp. 11 +/- 11, 59 +/- 2, 80 +/- 3, and 87 +/- 2% (P > 0.1, n = 7). Intra-brachial infusion of diazepam and midazolam resulting in forearm concentrations in the high therapeutic range does not augment adenosine-induced forearm vasodilation. A possible interaction at supra-therapeutic levels of the benzodiazepines can not be excluded from the present study, but lacks clinical significance