A sheep preparation for studying interactions between blood flow and drug disposition. II: Experimental applications

A sheep preparation has been developed which allows systematic direct studies into the sites and rates of distribution, formation and elimination of both endogenous and exogenous substances and their metabolites. Examples of some experimental applications are presented which provide information not usually available using traditional methods. Substantial metabolism at sites not usually regarded as important (e.g. limbs, lungs) was shown both for exogenous substances (procainamide and chlormethiazole) and for an endogenous substance (choline). Studies on drug clearance by kidney (cefoxitin), liver (chlormethiazole, pethidine and the optical isomers of mepivacaine) and lung (chlormethiazole) demonstrate that simple first-order elimination should not routinely be assumed to occur, as multiple sites and pathways may be involved, and kinetics may be non-linear as a result of characteristics of both organ flow and organ function. It was also shown that large changes (up to three-fold) in arterial blood drug concentrations may occur because of exogenous (anaesthesia) and endogenous (gastric recycling) perturbations, and that simple compartmental kinetics should not be assumed for either the whole body or individual organs. This preparation may be used in conjunction with traditional pharmacokinetic methods to resolve complex problems relating to interactions between drugs and the body, to establish a data base for physiological models of drug disposition, and to gain practical insights for drug treatment in patients.