Theoretical aspects of P-glycoprotein mediated drug efflux on the distribution volume of anaesthetic-related drugs in the brain

Publisher's copy made available with the permission of the publisher © Australian Society of AnaesthetistsP-glycoprotein in the membranes of endothelial cells actively transports some drugs out of the brain. The theoretical effect of P-glycoprotein mediated drug efflux on the cerebral distribution volumes of drugs was examined, with particular emphasis on anaesthetic-related drugs (often characterized by moderate to high permeability across the blood brain barrier due to their lipophilicity and intermediate molecular weight). An analytical equation for the cerebral distribution volume in the presence of the efflux was derived, and validated by modelling the same system using differential equations. The efflux was shown to lower both the membrane and intracellular drug concentrations in parallel, and to reduce the time required for brain:blood equilibration. The net effect of the efflux was governed by the ratio of the P-glycoprotein drug clearance from the membrane (Pcl) and the permeability of the membrane (PS). It was therefore a balance between the rate that a drug could be pumped out of the membrane by the efflux system, and the rate that the drug leaked back in due to the permeability of the membrane for the drug. The effect of the efflux was therefore more pronounced for drugs with membrane-limited cerebral kinetics (e.g. morphine), but was nevertheless significant for drugs with more flow-limited kinetics (e.g fentanyl). The cerebral distribution volume was also influenced by the free fraction in blood and the free fraction in the intracellular space in the conventional manner. There are no theoretical limitations to the P-glycoprotein system influencing the cerebral distribution volume of moderately lipophilic anaesthetic-related drugs.http://www.aaic.net.au/Article.asp?D=200114

Where's the Beef? How Much Can We Skimp on Pharmacokinetic-Pharmacodynamic Data?

Perioperative Medicine: Efficacy, Safety and Outcom

Combined Recirculatory-compartmental Population Pharmacokinetic Modeling of Arterial and Venous Plasma S(+) and R(-) Ketamine Concentrations

Perioperative Medicine: Efficacy, Safety and Outcom

Ketamine Psychedelic and Antinociceptive Effects Are Connected

Background: Ketamine produces potent analgesia combined with psychedelic effects. It has been suggested that these two effects are associated and possibly that analgesia is generated by ketamine-induced dissociation. The authors performed a post hoc analysis of previously published data to quantify the pharmacodynamic properties of ketamine-induced antinociception and psychedelic symptoms. The hypothesis was that ketamine pharmacodynamics (i.e., concentration-effect relationship as well as effect onset and offset times) are not different for these two endpoints. Methods: Seventeen healthy male volunteers received escalating doses of S- and racemic ketamine on separate occasions. Before, during, and after ketamine infusion, changes in external perception were measured together with pain pressure threshold. A population pharmacokinetic-pharmacodynamic analysis was performed that took S- and R-ketamine and S- and R-norketamine plasma concentrations into account. Results: The pharmacodynamics of S-ketamine did not differ for antinociception and external perception with potency parameter (median [95% CI]) C-50, 0.51 (0.38 to 0.66) nmol/ml; blood-effect site equilibration half-life, 8.3 [5.1 to 13.0] min), irrespective of administration form (racemic ketamine or S-ketamine). R-ketamine did not contribute to either endpoint. For both endpoints, S-norketamine had a small antagonistic effect. Conclusions: The authors conclude that their data support an association or connectivity between ketamine analgesia and dissociation. Given the intricacies of the study related to the pain model, measurement of dissociation, and complex modeling of the combination of ketamine and norketamine, it is the opinion of the authors that further studies are needed to detect functional connectivity between brain areas that produce the different ketamine effects

Ketamine Pharmacokinetics A Systematic Review of the Literature, Meta-analysis, and Population Analysis

Background: Several models describing the pharmacokinetics of ketamine are published with differences in model structure and complexity. A systematic review of the literature was performed, as well as a meta-analysis of pharmacokinetic data and construction of a pharmacokinetic model from raw data sets to qualitatively and quantitatively evaluate existing ketamine pharmacokinetic models and construct a general ketamine pharmacokinetic model.Methods: Extracted pharmacokinetic parameters from the literature (volume of distribution and clearance) were standardized to allow comparison among studies. A meta-analysis was performed on studies that performed a mixed-effect analysis to calculate weighted mean parameter values and a meta-regression analysis to determine the influence of covariates on parameter values. A pharmacokinetic population model derived from a subset of raw data sets was constructed and compared with the meta-analytical analysis.Results: The meta-analysis was performed on 18 studies (11 conducted in healthy adults, 3 in adult patients, and 5 in pediatric patients). Weighted mean volume of distribution was 252 l/70 kg (95% CI, 200 to 304 l/70 kg). Weighted mean clearance was 79 l/h (at 70 kg; 95% CI, 69 to 90 l/h at 70 kg). No effect of covariates was observed; simulations showed that models based on venous sampling showed substantially higher context-sensitive half-times than those based on arterial sampling. The pharmacokinetic model created from 14 raw data sets consisted of one central arterial compartment with two peripheral compartments linked to two venous delay compartments. Simulations showed that the output of the raw data pharmacokinetic analysis and the meta-analysis were comparable.Conclusions: A meta-analytical analysis of ketamine pharmacokinetics was successfully completed despite large heterogeneity in study characteristics. Differences in output of the meta-analytical approach and a combined analysis of 14 raw data sets were small, indicative that the meta-analytical approach gives a clinically applicable approximation of ketamine population parameter estimates and may be used when no raw data sets are available.Perioperative Medicine: Efficacy, Safety and Outcom