Pharmacology in Drug Discovery–Understanding Drug Response by Terry P. Kenakin

Author:Terry P. Kenakin
Language: eng
Format: epub
ISBN: 9780123848574
Publisher: Academic Press
Published: 2012-06-13T16:00:00+00:00

There can be dissimulations between the concentration of inhibitor in the extracellular space (delivered by pharmacokinetics from the central compartment; see Chapter 7 and Chapter 8) and the actual concentration of the inhibitor at the enzyme. For example, if diffusion into the cell is slow and the clearance from the body is rapid, then the concentration in the cell available for enzyme inhibition may be chronically lower than the peak levels of drug in the plasma. Figure 6.12 shows the effect of restricted diffusion of an enzyme inhibitor into the cell. In the figure, [Ao] and [Ai] refer to the respective concentrations of inhibitor outside and inside the cell. It can be seen that as the rate constant for cell entry (kin) diminishes, the deficit between the inside and outside concentrations increases. While this deficit can be overcome by very high levels of inhibitor, there is a concentration range whereby extracellular drug levels are not reflected inside the cell; this would cause subsequent lower therapeutic inhibition for an intracellular enzyme. Box 6.6 gives an example of how the therapeutic effects of an anti-cancer drug are completely controlled by how well the drug can access the enzyme in the cell.

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