Investigating the role of drug transporters in furosemide absorption, food-effect and elimination by a proteomics informed-mechanistic PBPK modeling approach

Abstract

Furosemide is a widely used diuretic for treating excessive fluid accumulation caused by disease conditions like heart failure and liver cirrhosis. Furosemide exhibits variable pharmacokinetics (PK) with bioavailability ranging from 10-100%, which is attributed to its low solubility and low permeability. Furosemide also shows moderate negative food effect despite of its higher solubility in fed-condition. To explain these clinical observations, we hypothesized that transporter mediated permeability plays a significant role in variable absorption, food effect and elimination of furosemide. To test this, we i) characterized the role of intestinal efflux transporters in furosemide absorption including food-effect and ii) predicted the contribution of renal uptake and efflux transporters on its disposition by using a proteomics-informed mechanistic physiologically based pharmacokinetic (PBPK) modeling. Our in vitro results confirmed that furosemide is a substrate of various intestinal transporters, i.e., BCRP, MRP4 and OATP2B1. The PBPK model suggests that fasting condition leads to saturation of BCRP because of the faster gastric emptying. On the other hand, delayed gastric emptying allows efficient BCRP mediated furosemide efflux in fed condition, hence explains the negative food effect. The study could be further extended to test the effect of BCRP, MRP4 and OATP2B1 genetic polymorphisms or drug-interactions on absorption, disposition, efficacy and toxicity of furosemide. Further, as furosemide has been proposed as a probe substrate of renal organic anion transporters (OATs) for assessing clinical drug-drug interactions (DDIs) during drug development, the confounding effects of intestinal transporters on furosemide PK should be considered while interpreting such clinical transporter DDI studies.