Pharmacokinetic considerations of regional administration and drug targeting: influence of site of input in target tissue and flux of binding protein.

Hunt et al. introduced the concept of the Drug Targeting Index (DTI) to quantify the gain associated with regional drug administration and targeting and showed that for the ideal case of all drug first reaching the target DTI = l + CLs/(QT(l-ET)) where CL, is the total clearance of drug from the body (including the target tissue). QT is the target blood flow and ET is the steady-state extraction ratio of the drug in the target. In the model they portrayed the tissue as a homogeneous organ. A more general pharmacokinetic model has been developed that takes into account the three anatomical spaces (vascular, interstitial, and intracellular) of the target organ or tissue and that, in addition to unbound drug permeating the vascular and cellular membranes, protein-bound drug can also flux between the vascular and interstitial spaces. Elimination of unbound drug can take place from the cellular and interstitial spaces. An important parameter influencing the DTI is shown to be the fraction of targeted dose that is eliminated there before it reaches the systemic circulation, fT. Equations have been developed showing the relationship between fT and ET and for DTI when drug is administered at the various sites within the tissue and under a variety of conditions. Only when drug is administered into the target arterial blood stream or when distribution of drug within the target tissue is perfusion rate-limited, does fT = ET and DTI = 1 + CLs/x (QT (I - ET)). Otherwise consideration needs to be given to the permeabilities of both the unbound and bound drug and site of target administration, interstitial or intracellular. Then fT is greater than ET and DTI is greater than that expected had perfusion-rate limited distribution prevailed. The maximum benefit in DTI is seen for a drug of low cellular permeability but high cellular intrinsic clearance administered intracellularly.