Peter Krajcsi
Solvo Biotechnology, Hungary
Title: Role of transporters in permeability of drugs – options for testing, modulation and targeting
Biography
Biography: Peter Krajcsi
Abstract
Physiological cellular barriers of pharmaceutical importance express a large number of membrane transporters. Most membrane transporters either catalyze cellular influx or cellular efflux but some are bidirectional. The role of membrane transporters in modulation of permeability is increasingly recognized and is particularly critical for BCS / BDDCS Clas II-IV drugs. There is a significant cross-talk between transporters and enzymes of xenobiotic metabolism. The two systems may play complementary or compensatory roles. A number of assay systems are available to study transporter – drug interactions as well as transporter mediated drug – drug interactions (tDDI). Cellular assays as well as membrane assays are available. It is important that the expression systems used in transfectants mimic the physiological membrane environment. Physicochemical properties of drugs are important determinants of assay selections as transcellular transport assays (monolayer assays) may work even for intermediate-to- high passive permeability drugs but may not work for low passive permeability drugs. In contrast, membane uptake assays are ideal for low passive permeability substrates. Apically located intestinal efflux transporters (e.g. P-gp, BCRP) may limit absorption of substrate drugs. Inhibition of the efflux transporters by excipients my increase absorption, bioavailability. Targeting influx transporters may increase absorption and may play a role in tissue targeting too. Importantly, low influx transporter expression in target cells / tissue may lead to resistance to substrate drugs. Exploratory strategies to target influx transporters expressed in the blood – brain barrier have been described.