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

Drug Disposition, Eli Lilly and Company, Indianapolis, Indiana (M.J.Z.-G., J.C.K.); and School of Pharmacy, the University of North Carolina, Chapel Hill, North Carolina (G.M.P., K.L.R.B.)

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.