The Necessity of Using Changes in Absorption Time to Implicate Intestinal Transporter Involvement in Oral Drug-Drug Inte
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Research Article The Necessity of Using Changes in Absorption Time to Implicate Intestinal Transporter Involvement in Oral Drug-Drug Interactions Jasleen K. Sodhi1
and Leslie Z. Benet1,2
Received 1 May 2020; accepted 3 June 2020 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 wellcharacterized clinical substrates and perpetrators to demonstrate how mean absorption time (MAT) and time to maximum concentration (tmax) 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 tmaxvalues, induction increased these values, while inhibition of intestinal metabolic enzymes did not result in altered MAT or tmax. 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. KEY WORDS: intestinal DDIs; absorption rate; MAT; tmax. 1
Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, 513 Parnassus Ave Rm HSE 1164, UCSF Box 0912, San Francisco, CA 94143, USA. 2 To whom correspondence should be addressed. (e–mail: [email protected]) Abbreviations: AUC, area under the curve; AUC0 → ∞, area under the curve extrapolated to infinity for a single dose; AUC0 → τ, area under the curve during a dosing interval at steady-state; AUCτ → ∞, area under the curve extrapolated from the end of the dosing interval to infinity at steady-state; AUMC, area under the moment curve; AUMC0 → ∞, area under the moment curve extrapolated to infinity for a single dose; AUMC0 → τ, area under the moment curve during a dosing interval at steady-state; BCRP, breast cancer resistance protein; BDDCS, Biopharmaceutics Drug Disposition Classification System; CL, clearance; CL/F, apparent clearance; CYP, cytochrome P450; DDI, drug-drug interaction; F, bioavailability; F
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