Systemic circulation, drug concentration

This postulated phenomenon can have the beneficial effect of reducing the likelihood of systemic side-effects by effectively buffering the rate at which the drag enters the systemic circulation and hence reducing peak-to-trough variations in concentration. Conversely, high affinity for Hver Hssue may increase exposure to the enzymes of clearance and may therefore attenuate the first-pass extraction of drugs. 

The IM and SC routes are by far the most frequently used extravascular parenteral routes of drug administration in farm animals. The less frequently used parenteral routes have limited application, in that they aim at directly placing high concentrations of antimicrobial agent close to the site of infection. These routes of administration include intra-articular or subconjuctival injection and intra-mammary or intra-uterine infusion. These local routes differ from the major parenteral routes in that absorption into the systemic circulation is not a prerequisite for delivery of drug to the site of action. The combined use of systemic and local delivery of drug to the site of infection represents the optimum approach to... 

The relevance of P-gp at the BBB is considered highly important due to the low drug concentrations in the systemic circulation. The interest in transporters led to development of cell lines that overexpress them, for example, MDCK-MDRl and MDCK-MDR2. MDCK-MDRl, which overexpresses P-gp, is one of the most widely used models in early drug discovery screening [38, 39]. 

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