Relationship between Drug/Metabolite Exposure and Impairment of Excretory Transport Function

Abstract

ABSTRACT:The quantitative impact of excretory transport modulation on the systemic exposure to xenobiotics and derived metabolites is poorly understood. This article presents fundamental relationships between exposure and loss of a specific excretory process that contributes to overall clearance. The mathematical relationships presented herein were explored on the basis of hepatic excretory data for polar metabolites formed in the livers of various transporter-deficient rodents. Experimental data and theoretical relationships indicated that the fold change in exposure is governed by the relationship, 1/(1 ؊ f e ), where f e is the fraction excreted by a particular transport protein. Loss of function of a transport pathway associated with f e < 0.5 will have minor consequences (<2-fold) on exposure, but exposure will increase exponentially in response to loss of function of transport pathways with f e > 0.5. These mathematical relationships may be extended to other organs, such as the intestine and kidney, as well as to systemic drug exposure. Finally, the relationship between exposure and f e is not only applicable to complete loss of function of a transport pathway but also can be extended to partial inhibition scenarios by modifying the equation with the ratio of the inhibitor concentration and inhibition constant.Quantitative methods to predict the change in drug exposure resulting from drug-drug interactions occurring at the level of excretory transport have not been fully developed. A fundamental understanding of the effect of excretory transport modulation on drug/metabolite exposure is presently lacking. Kinetic approaches originally used to examine issues related to drug metabolism, such as the relative activity factor method, are now being applied to transport processes (Hirano et al., 2004). In this article, the equation describing the effect of inhibition of drug metabolism on systemic concentrations (Rowland and Matin, 1973) is adapted to explore the effect of transport modulation on exposure.Hepatobiliary excretion data for polar metabolites generated in perfused livers of various transporter-deficient animals are used primarily in this article as supporting evidence for the theoretical equations. However, the relationships presented are applicable to any organ such as the intestine and kidney in which the formed metabolites can be excreted into two distinct compartments. Most importantly, the relationship describing the fold change in exposure is applicable not only to an isolated organ but also to the systemic exposure of drugs and metabolites when systemic clearance is mediated by excretory transport. This article provides proof that the maximum fold change in exposure to a drug or metabolite cleared by active excretion is dictated by the relationship 1/(1 Ϫ f e ), where f e is the fraction of total clearance mediated by the ablated transport protein. Although the equations presented may seem to be theoretically obvious, extensive experimental proof of these relationships currently does not exist...

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