UCSF

Introduction

In drug discovery and development, it is of high interest to characterize the potential for intestinal drug-drug interactions to alter bioavailability of a victim drug. For drugs that are substrates of both intestinal transporters and enzymes, estimating the relative contribution of each process has proved challenging, especially since the susceptibility of drug to uptake or efflux transporters in vitro does not always translate to clinically significant in vivo involvement. Here we introduce a powerful methodology to implicate intestinal transporters in drug-drug interactions based on the theory that clinically relevant intestinal transporter interactions will result in altered rate of absorption of victim drugs.

Methods and materials

We present exemplary clinical drug-drug interaction studies that utilize well-characterized clinical substrates and perpetrators to demonstrate how mean absorption time (MAT) and time to maximum concentration (t_max) are expected to change (or remain unchanged) when either intestinal transporters or metabolic enzymes were/are altered. Apixaban was also selected to demonstrate the utility of the methodology, as the purported involvement of both intestinal enzymes and transporters has been suggested in its FDA package insert.

Results and discussion

Acute inhibition of gut efflux transporters resulted in decreased MAT and t_maxvalues, induction increased these values, while inhibition of intestinal metabolic enzymes did not result in altered MAT or t_max. Involvement of intestinal efflux transporters in apixaban disposition is unlikely.

Conclusion

Utilization of this simple but powerful methodology to implicate intestinal transporter involvement will have significant impact on how drug-drug interactions are interpreted.