Pharmacokinetic-Pharmacodynamic Modeling of the D2 and 5-HT2A Receptor Occupancy of Risperidone and Paliperidone in Rats

A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of brain concentration and dopamine D-2 and serotonin 5-HT2A receptor occupancy (RO) of the atypical antipsychotic drugs risperidone and paliperidone in rats. A population approach was utilized to describe the PK-PD of risperidone and paliperidone using plasma and brain concentrations and D-2 and 5-HT2A RO data. A previously published physiology- and mechanism-based (PBPKPD) model describing brain concentrations and D-2 receptor binding in the striatum was expanded to include metabolite kinetics, active efflux from brain, and binding to 5-HT2A receptors in the frontal cortex. A two-compartment model best fit to the plasma PK profile of risperidone and paliperidone. The expanded PBPKPD model described brain concentrations and D-2 and 5-HT2A RO well. Inclusion of binding to 5-HT2A receptors was necessary to describe observed brain-to-plasma ratios accurately. Simulations showed that receptor affinity strongly influences brain-to-plasma ratio pattern. Binding to both D-2 and 5-HT2A receptors influences brain distribution of risperidone and paliperidone. This may stem from their high affinity for D-2 and 5-HT2A receptors. Receptor affinities and brain-to-plasma ratios may need to be considered before choosing the best PK-PD model for centrally active drugs

Functional imaging of P-glycoprotein in the blood-brain barrier with PET: State of the art

The blood-brain barrier (BBB) is the main barrier between blood and brain. Its purpose is to maintain homeostasis in and protection of the central nervous system. Therefore, under normal physiological conditions, the BBB is impermeable for endotoxins, but also for exotoxins like drugs. In the endothelial cells of the BBB, different active influx, but also active drug efflux transporters are presents. An example of drug efflux pumps is P-glycoprotein (P-gp) drug efflux pumps, which are encoded by MDR1 genes in humans. A different P-gp expression in the blood-brain barrier can play a role in the aetiology of several brain disorders. For this reason, there is a need to develop an assay for the quantification P-gp functionality in the BBB. We discuss, the relationship of P-gp and brain pathology and the involvement of age in loss of P-gp function. Furthermore, drugs treatment of brain diseases like Alzheimers's disease and Parkinson's disease are often not effective. Therefore, we discuss the relationship between P-gp and drug availability. In this chapter, an overview is given in the use of positron emission tomography as a tool for measuring P-gp function in the area of neurology, neurophysiology and pharmacology