Free drug concentration

Measurement of free drug concentration in the receptor compartment (2.11.4)... 

Measurement of Free Drug Concentration in the Receptor Compartment... 

Free drug concentration description of, 36-37 measurement of, in receptor compartment, 39 Frovatriptan, 163f Full agonism, 200-202 Full agonists affinity of, 261 description of, 27—30 dose-response curves for, 90, 200-202 Furchgott method for affinity measurements, 261 potency ratios for, 202—204, 219—220 Functional assays... 

Receptor assays, 251 Receptor compartment definition of, 35 drug removal from, 36f free drug concentration in, 39 Receptor density... 

Cf = free drug concentration in compartment x of tissue i, moles per unit volume... 

Combined use of Eqs. (43)—(45) allows free drug concentrations to be predicted for each subcompartment. This approach to modeling free drug concentrations would make use of protein binding parameters (i.e., Bt, Kt) obtained from in vitro experiments. 

Figure 35 Relationship between the uptake permeability coefficient and the free drug concentration. PAEL is the permeability of the free drug across the aqueous boundary layer, and P BL is the same for the drug-albumin complex. [Redrawn from Raub et al. (1993) with permission from the publisher.]...

A number of recent publications indicate that the antibacterial field has adopted the concept of comparing free drug concentration at the site of action to in vitro drug potency reported as MIC [24-26]. A study of the antibacterial ertapenem in healthy volunteers was carried out to provide support for its use in skin and skin-structure infections [27]. Using microdialysis techniques, unbound drug concentrations in muscle and subcutaneous tissues were sampled at... 

Intracellular targets can present a more complex situation with respect to the application of the free drug principle. The unavailability of reliable general methods for determining free drug concentrations inside the cell (as opposed to total drug associated with the cell, which can usually be measured), often renders... 

A recent report on a NR2B selective NMDA receptor antagonist (9) supports the findings of Kalvass and Maurer [56], Rapid equilibration between plasma and CNS coupled with the lack of Pgp substrate activity led the authors to assume that plasma-free and brain-free drug concentrations were equivalent. An ex vivo receptor binding assay showed 50% occupancy at a total plasma concentration of 230 nM. Given a rat-free fraction of 15.3%, the authors concluded that 50% brain occupancy occurred at 35 nM unbound brain concentration, which was in reasonable agreement with the measured Ki of 3.4 nM versus the human receptor. 

Fig. 2.10 Correlation of in vitro potency with plasma free drug concentration required for efficacy.

The use of microdialysis has enabled unbound drug concentrations to be determined in ECF, providing another measurement of penetration across the blood-brain barrier and one more closely related to activity. A review of data obtained by microdialysis [7], showed that free drug exposure in the brain is equal to or less than free drug concentration in plasma or blood, with ratios ranging from 4% for the most polar compound (atenolol) to unity for lipophilic compounds (e.g. carbamazepine). This largely supports the similar conclusions from the CSF data shown above. This relationship is illustrated in Figure 4.4. 

B) The relative free drug concentration of both compounds is unchanged. 

The thickness of the tissue, partition coefficient, and the diffusion coefficient are properties of the mucosa and cannot be altered. Designing appropriate formulations that heed the necessary conditions can vary the surface area for delivery of the drug, time of contact, and the free drug concentration. The partitioning of the drug into the membrane will depend on... 

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