Received for publication August 17, 2007.
Revised January 9, 2008.
Accepted for publication January 14, 2008.

The Role of Efflux and Uptake Transporters in Lapatinib (Tykerb, GW572016) Disposition and Drug Interactions

Abstract

Lapatinib is a tyrosine kinase inhibitor approved for use in combination with capecitabine to treat advanced or metastatic breast cancers over expressing HER2 (ErbB2). This work investigated the role of efflux and uptake transporters in lapatinib disposition and drug interactions. In vitro studies evaluated whether lapatinib is a substrate for efflux transporters, or an inhibitor of efflux/uptake transporters. In vivo studies included whole-body autoradiography (WBA) and an evaluation of the role of efflux transporters on the intestinal absorption and brain penetration of lapatinib using chemical or genetic knock-out animals. Lapatinib is a substrate for the efflux transporters P-glycoprotein (Pgp) and Breast Cancer Resistance Protein (BCRP). Further, lapatinib is an inhibitor (IC50 values 0.025 to 5 uM) of Pgp, BCRP and OATP1B1 (a hepatic uptake transporter). In contrast, lapatinib yielded little inhibition of renal transporters (OATs, OCTs, URAT). In vivo studies demonstrated that brain concentrations of lapatinib were low and influenced by efflux transporters at the blood-brain barrier. In contrast, lapatinib's systemic exposure after oral dosing was unchanged when efflux by Pgp and BCRP was absent from the gastrointestinal tract. These in vitro and in vivo preclinical investigations provide a mechanistic basis for elucidating clinical drug interactions.

Key words: ABC transporters, absorption, anticancer agents, drug disposition, drug-drug interactions, membrane permeability, organic anion transport, organic cation transport, p-glycoprotein, transporters