2019 PharmSci 360
Susceptibility of drug to uptake or efflux transporters in vitro does not always translate to clinically significant in vivo involvement. Following orally dosed drug-drug interaction(DDI) studies, separating changes in clearance(CL) or volume(V) from bioavailability(F), as well as consideration of the impact of both CL and V on half-life changes, makes discerning whether transporter involvement is significant a difficult task. By examining the change in mean absorption time(MAT), it is possible implicate transporter involvement in an oral DDI study, with significant changes indicating intestinal drug transport has altered, and no change indicating no transporter involvement. For instance, when rifampin(widely-used transporter inhibitor) was administered IV in combination with rosuvastatin(known transporter substrate), MAT decreased 2.1-and 2.9-fold in Whites and Asians, respectively. However, although apixaban has been implicated in vitro as a PGP and BCRP substrate, examination of 5 clinical DDI studies shows no change in MAT(ratios ranging from 0.92-1.04), indicating insignificant transporter involvement.