Membrane transporters play an important role in intestinal absorption, distribution and clearance of drugs.
Additionally transporters along with enzymes regulate tissue exposures (e.g. liver, kidney and brain), which are important
for safety and efficacy considerations. Early identification of transporters involved guides generation of in vitro and in
vivo data needed to gain mechanistic understanding on the role of transporters in organ clearance, tissue exposures and
enables development of physiological-based pharmacokinetic (PBPK) models. A lot of progress has been made in
developing several in vitro assay systems and mechanistic in silico models to determine kinetic parameters for
transporters, which are incorporated into PBPK models. Although, intrinsic clearance and inhibition data from in vitro
systems generally tend to underpredict in vivo clearance and magnitude of drug-drug interactions (DDIs), empirical
scaling factors derived from a sizable dataset are often used to offset underpredictions. PBPK models are increasing used
to predict the impact of transporters on intestinal absorption, clearance, victim and perpetrator DDIs prior to first in
human clinical trials. The models are often refined when clinical data is available and are used to predict
pharmacokinetics in untested scenarios such as the impact of polymorphisms, ontogeny, ethnicity, disease states and DDIs
with other perpetrator drugs. The aim of this review is to provide an overview of (i) regulatory requirements around
transporters, (ii) in vitro systems and their limitations in predicting transporter mediated drug disposition and DDIs, (iii)
PBPK modelling tactics and case studies used for internal decision making and/or for regulatory submissions.