Interplay of transporters and enzymes in drug and metabolite processing

This review highlights the "interplay" between enzymes and transporters, essential components of eliminating organs for drug removal. The understanding of the interplay is important in terms of deciphering the change of one eliminatory pathway on compensatory mechanisms in drug disposal, and, ultimately, their importance in drug-drug interactions. Controversy existed on the explanation underlying the interplay between transporters and enzymes in the Caco-2 cell monolayer or cell culture systems, but less so on eliminating organs such as the intestine and liver. For the Caco-2 system, the increase in the mean residence time (MRT) accompanying increased secretion had been construed as the basis for increased metabolism. We hold the opposite view and assert that increased secretion should evoke a decrease in metabolism due to the competition between the enzyme and apical efflux transporter for the drug within the cell. To illustrate this point, simulations on the MRT, fraction of dose metabolized (f(met)) and the extraction ratio (ER) as defined by various investigators under linear and nonlinear metabolic conditions were compared to observed data and the trends upon induction/inhibition of secretion. The conclusion is that the f(met) is the more appropriate index to reflect the extent of metabolism in transporter-enzyme interplay, since the parameter captures drug metabolism in the cell when its contents in the apical, cell, and basolateral compartments or the entire dose is considered to be available for metabolism. This parameter for metabolism (f(met)) bears a reciprocal relationship to the secretory intrinsic clearance and is in concordance with the notion that both the enzyme and apical transporter compete for the cellular substrate within. For the liver and intestine, several physiologically based pharmacokinetic (PBPK) models that contain transporters and enzymes were utilized, together with the solved equations for the area under the curve (AUC), metabolic, excretory, and total clearance (CL) to shed meaningful insight of how the inhibition of one pathway can result in a higher AUC and therefore a reduced total clearance for drug, but a higher apparent clearance of the alternate pathway; induction of the same pathway would lead to an increased total clearance but decreased drug AUC, and reduced clearance of the alternate pathway. The use of an increased MRT to explain increased extents of metabolism upon increased apical excretion is not tenable in these organs or "open systems" since the MRT of drug in the cell is reduced with irreversible loss from biliary excretion or hastened gastrointestinal transit of the secreted drug in the lumen. Data in the literature for the Caco-2 system, knockout animals and organ perfusion systems were discussed in relation to these concepts on clearance based on fundamental, pharmacokinetic theory. The shortcomings in data interpretation were discussed. The general conclusion is that a reciprocal relationship exists between the clearances related to enzymes and apical transporters due to their competition for the substrate within the cell, and is a relationship independent of the MRT of drug in the system.