Receptor biophase

Factors That Influence Purine Concentration in the Receptor Biophase.356... 

Different types of adenosine and P2Y receptors may be present in the same nerve terminal. The effect that prevails may be determined by the functional interaction, in the receptor biophase, between purine release, uptake and metabolism. 

The coexistence of inhibitory and facilitatory adenosine- and P2-receptors in the same nerve terminal raises the question of which factors influence the concentration of endogenous agonists in the vicinity of each receptor (i.e., in the receptor biophase) and, consequently, determine the net modulatory effect. Tissue differences in receptor expression and purine release/formation or inactivation systems create a diversity of possibilities that makes the net modulatory effect by endogenous purines quite variable from tissue to tissue. 

The concentration of adenosine in the PI receptor biophase and the balance between Ai and A2a receptor-mediated effects is influenced by the adenosine inactivation systems (ADA and the adenosine uptake carriers see Figure4d). Ai receptors are surface anchoring proteins for ecto-ADA, and binding of ecto-ADA to Ai recep-... 

Fig. 4 Mechanisms involved in the extracellular inactivation of nucleotides (a, b and c) and adenosine (d) and their influence on purine concentration in the P2Y and PI receptor biophases, (a) NT-PDasel hydrolyses ATP and ADP very efficiently, thus preventing their action on P2Y receptors (b) NTPDase2 metabolizes ATP preferentially, allowing an accumulation of ADP and thus favouring activation of P2Yi, 12,13 receptors (c) NTPDase3 hydrolyses both ATP and ADP slowly, giving them time to activate both P2Y2,4 and P2Y 1,12,13 receptors. Formation of adenosine depends on the activity of ecto 5 -nucleotidase (CD73). Adenosine inactivation systems also influence adenosine concentration in the PI receptor biophase (d) the nucleoside transporters take up adenosine adenosine deaminase (ADA) regulates both the concentration of adenosine in the Ai receptor biophase and the functionality of Ai receptors.

In some cases barriers such as the blood-brain barrier exist, in other cases the target is intracellular. Here the model has to be extended to place the receptor in a biophase... 

To understand drug-receptor interactions, it is necessary to quantify the relationship between the drug and the biological effect it produces. Since the degree of effect produced by a drug is generally a function of the amount administered, we can express this relationship in terms of a dose-response curve. Because we cannot always quantify the concentration of drug in the biophase in the intact individual, it is customary to correlate effect with dose administered. 

If the antagonism is of the equilibrium type, the antagonism increases as the concentration of the antagonist increases. Conversely, the antagonism can be overcome (surmounted) if the concentration of the agonist in the biophase (the region of the receptors) is in-... 

The interactions between transmitters and their receptors are readily reversible, and the number of transmitter-receptor complexes formed is a direct function of the amount of transmitter in the biophase. The length of time that intact molecules of acetylcholine remain in the biophase is short because acetylcholinesterase, an enzyme that rapidly hydrolyzes acetylcholine, is highly concentrated on the outer surfaces of both the prejunctional (neuronal) and postjunctional (effector cell) membranes. A rapid hydrolysis of acetylcholine by the enzyme results in a lowering of the concentration of free transmitter and a rapid dissociation of the transmitter from its receptors little or no acetylcholine escapes into the circulation. Any acetylcholine that does reach the circulation is immediately inactivated by plasma esterases. 

Like the cholinergic transmitter, the noradrenergic transmitter is released by action potentials through ex-ocytosis, the contents of entire vesicles being emptied into the biophase (synaptic or junctional region). Similarly, the formation of transmitter-receptor complexes is a direct function of the concentration of transmitter in the biophase and is readily reversible. In this instance, the receptors are adrenoceptors. 

Once administered, by whatever route, a drug must usually cross one or more membranes before the required biophase and target receptor are reached. Design principles can be applied to help access the biophase, and depend on knowledge of the mechanisms involved. 

Danhof, M., de Jongh, J., De Lange, E. C., Della Pasqua, O., Ploeger, B. A., Voskuyl, R. A. Mechanism-based pharmacokinetic-pharmacodynamic modeling biophase distribution, receptor theory, and dynamical systems analysis. Anna Rev Pharmacol Toxicol 2007,47 357-400. 

The effect-compartment model relaxes the assumption H3 and it stems from the assumption of prereceptor nonequilibrium between drug concentration in the blood or plasma c (t) and the receptor site y (t). According to this model, an additional compartment is considered, the effect (or biophase) compartment, and... 

Pharmacodynamics describes the time course and the magnitude of pharmacological response of drugs. Based on the classic receptor-occupancy theory, after drug molecules reach the target biophase, it binds to the receptors to form the drug-receptor complex to exert pharmacological response (Fig. 2). 

Many correlations of biological activity with logP are nonlinear, and show maximal activity at an optimal value for the partition coefficient, logPQ. This prompted Hansch (114) to suggest that the partition coefficient not only describes the hydrophobic interaction between molecules and the biophase (e.g., membranes, receptors) but also their ability to permeate through membranes. 

Danhof, M. et al., Mechanism-based pharmacokinetic-pharmacodynamic modeling Biophase distribution, receptor theory, and dynamical systems analysis. Annu. Rev. 

Ideally, concentrations should be measured at the effect site, the site of action, or biophase, where the interaction with the respective biological receptor system takes... 

Although the pharmacodynamic effect is primarily a function of the concentration of a drug at the site of action and the affinity of the drug for the receptors, time-dependent processes such as ADME also influence the observed effect. Consequently, the pharmacodynamic effect is also a function of time, especially under in vivo conditions where drug molecules may not equilibrate rapidly with the biophase. Recently, relationships between plasma concentrations of drugs and pharmacodynamic effects have received considerable attention. The mathematical analysis of the relationships between pharmacokinetics and pharmacodynamics is often termed... 

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