Excretion or elimination of a compound and its metabolites typically occurs via the urine or feces or both routes. Far from being a "waste", understanding the kinetics of drug elimination is key to predicting the dose strength and dose frequency to be used in clinical studies.
Allometric scaling can be used to predict elimination rates in humans, based on the known elimination rates in a preclinical species such as the rat. Allometric scaling relationships have been published for rat versus human clearance data for a number of different drugs (see, for example, Lin, 1995 and Chiou et al., 1998). These allometric relationships allow prediction of human renal (kidney-specific) or systemic (total) clearance from rat data within a factor of two or three, supporting the usefulness of rat pharmacokinetic (PK) studies in drug development.
Absorption Systems offers in vivo PK studies in rats, dogs and several other preclinical species to help predict human clearance of compounds. In addition, we can model passive urinary excretion by measuring protein binding in rat and human plasma, then scaling up from rat to human using constants that take into account the differences in body mass, glomerular filtration rate, etc.
Mechanisms of active urinary excretion and reabsorption are difficult to model in vivo due to differences in transporters across species. But they are important to understand due to the potential for drug-drug interactions and nephrotoxicity resulting from inhibition of transporters in the kidney. For this, we offer in vitro, cell-based models, which can provide detailed mechanistic information. Far from being a "waste", understanding the kinetics of drug elimination is key to predicting the dose strength and dose frequency to be used in clinical studies. We use MDR1-MDCK, a cell line in which P-glycoprotein (P-gp) is overexpressed, to study the involvement of P-gp in drug excretion and potential drug-drug interactions.
Biliary excretion is a complex process involving multiple transporters and numerous points of potential drug-drug interactions and hepatotoxicity, one mechanism being alteration of bile salt composition (Trauner and Boyer, 2003). This is an area in which in vitro to in vivo correlations are difficult. Saturable membrane transport mechanisms can be involved on both sides of this biological equation, and their involvement can be elucidated by carrying out studies in the presence and absence of transport inhibitors.
