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Incorporation of transporter effects
Intestinal transporter-mediated efflux can play a significant role in the oral bioavailability of some drugs by limiting their entry into the systemic circulation, although many substrates have no bioavailability problems due to adequate passive permeability. Furthermore, influx and efflux transport in the liver can also have a significant impact on drug disposition.
The physiologically-based pharmacokinetic models within Simcyp can accommodate the effects of saturable influx and efflux transporters in both the intestine and liver. In addition, drug-drug interactions involving transporters can also be investigated.
Transporter-based drug interactions is currently a hot topic with the regulators and a recent paper by Zhang et al. provides the FDA’s viewpoint on the subject. The authors provide information needed during drug development and in new drug application (NDA) submissions and explain the criteria that may warrant conduct of in vivo P-gp-mediated drug interaction studies based on in vitro assessment.
Transporters available within the Simcyp Simulator include P-gp, BCRP and MRP2, in both the gut and liver, and OATP1B1, OATP1B3 and OCT1 in the liver. Users can also define their own influx transporter to simulate the effects of drug uptake in the intestine.
