Summary

The classical pharmacokinetic phase/pharmacodynamic phase model of dose response can be represented physiologically by considering each component of the phases being separated by lipid membrane barriers that may or may not possess aqueous channels (pores) and which divide essentially aqueous environments. By studying only steady state conditions, the only interactions that need to be considered are how drug molecules traverse the compartments and how they interact with the proteins that trigger pharmacological activity (target) or metabolise and excrete them. The free concentration of drug in the plasma is in direct equilibrium with the interstitial fluid bathing most cells of the body, since the capillary wall contains sufficient pores to allow the rapid passage of relatively small molecules, regardless of physicochemistry. Such aqueous channels are much fewer in number in the capillaries of the brain (blood brain barrier) and rapid transfer into the brain fluids requires molecules to traverse the lipid cores of the membranes. Actual passage into cells requires the molecules to also transit the lipid core of the membrane. Distribution to the target for a drug, for instance whether a cell membrane receptor or an intracellular enzyme, therefore determines the range of physicochemical properties available for the drug discoverer to exploit The concentration of free drug in plasma is governed by the rate of delivery and the rate of clearance. Clearance of drug normally occurs from the liver and kidneys and it is an important assumption that only the free drug is available for clearance. lipophilic drugs are metabolised by intracellular membrane bound enzyme systems (e.g. cytochrome P450's) and glucuronyl transferases) to more water soluble derivatives. The active sites of the major forms of the cytochrome P-450 superfamily rely heavily on hydrophobic interactions with their substrates although ion-pair and hydrogen braiding interactions also occur. Exit from the hepatocyte may be by simple passive diffusion back into the plasma or via cannicular active transport systems which excrete drugs and their metabolites, again with wide ranging physical properties, into the bile. Glomerular filtration by the kidney, of free drug in plasma, does not pose physicochemical barrier, so that all small molecules, with relatively low molecular weight, will appear in the filtrate. The secretion of drugs into the urine can also occur through tubular carrier systems similar to those present on the sinusoid face of the hepatocyte. The aqueous concentration processes that occur in the kidney mean that for drugs capable of travelling through the lipid core of the tubule membrane, significant reabsorption back into the plasma will occur. This process has the end result of only hydrophilic molecules being voided in the urine to any substantial degree. Our understanding of the various processes suggest that expert systems could be developed to predict dose response from minimal in vitro data.