Intestinal Drug Interactions Mediated by OATPs: A Systematic Review of Preclinical and Clinical Findings

Abstract

In recent years, an increasing number of clinical drug–drug interactions (DDIs) have been attributed to inhibition of intestinal organic anion-transporting polypeptides (OATPs); however, only a few of these DDI results were reflected in drug labels. This review aims to provide a thorough analysis of intestinal OATP-mediated pharmacokinetic-based DDIs, using both in vitro and clinical investigations, highlighting the main mechanistic findings and discussing their clinical relevance. On the basis of pharmacogenetic and clinical DDI results, a total of 12 drugs were identified as possible clinical substrates of OATP2B1 and OATP1A2. Among them, 3 drugs, namely atenolol, celiprolol, and fexofenadine, have emerged as the most sensitive substrates to evaluate clinical OATP-mediated intestinal DDIs when interactions with P-glycoprotein by the test compound can be ruled out. With regard to perpetrators, 8 dietary or natural products and 1 investigational drug, ronacaleret (now terminated), showed clinical intestinal inhibition attributable to OATPs, producing ≥20% decreases in area under the plasma concentration–time curve of the co-administered drug. Common juices, such as apple juice, grapefruit juice, and orange juice, are considered potent inhibitors of intestinal OATP2B1 and OATP1A2 (decreasing exposure of the co-administered substrate by ∼85%) and may be adequate prototype inhibitors to investigate intestinal DDIs mediated by OATPs.

Introduction

Organic anion-transporting polypeptides (OATPs), transmembrane transport proteins categorized as members of the solute carrier (SLC) family, are localized in organs involved in drug elimination, such as the gastrointestinal tract, kidney, liver, blood–brain barrier, and elsewhere.¹ Among 11 individual human OATP transporters that comprise 6 families (OATP1-6), OATP1A2 and OATP2B1 are reportedly expressed in human intestine, although there are uncertainties regarding the expression level of OATP1A2 in the intestine.1, 2, 3, 4

Intestinal OATPs can facilitate the uptake of endogenous compounds and drugs into the intestine and, thus, contribute to intestinal drug absorption. In theory, any perpetrator that inhibits intestinal OATPs could reduce drug absorption and, thus, systemic exposure. Studies of drug–drug interactions (DDIs) associated with OATP1A2 and OATP2B1 have presented a number of challenges. Even when a drug has been identified as an OATP substrate, its rate and extent of drug absorption can be affected by many additional factors, such as efflux transport, drug dissolution, and extent of passive diffusion. Also, well-characterized clinical probe substrates and inhibitors for intestinal OATPs are lacking. Recently, evidence has accumulated suggesting that inhibition of intestinal OATP constitutes a mechanism of DDIs with potential efficacy implications. Several drugs from various therapeutic areas (e.g., aliskiren, fexofenadine, and nadolol) have been labeled as substrates of OATP2B1 and OATP1A2 as a result of significant decreases in exposure when co-administered with a variety of fruit juices and other dietary or natural products (e.g., green tea) that are known OATP inhibitors. Also, a number of pharmacogenetic (PGx) studies have investigated the impact of OATP polymorphisms on the pharmacokinetics (PK) of drugs, such as aliskiren, celiprolol, and montelukast (to be discussed subsequently). At present, neither the U.S. Food and Drug Administration (FDA), the European Medicines Agency, the Public Health Agency of Canada, nor the Japan Pharmaceuticals and Medical Devices Agency provide regulatory guidances regarding in vitro assays determining whether investigational drugs are substrates or perpetrators of intestinal OATPs.5, 6, 7, 8 This review was designed to provide a detailed analysis of the preclinical and clinical intestinal OATP-mediated PK-based DDIs published so far in the literature, including main mechanistic findings and clinical relevance. The analysis was performed using the University of Washington Drug Interaction Database (DIDB^®) drug interaction and PGx modules (http://www.druginteractioninfo.org). All in vitro kinetic and in vivo PK parameters were derived from the DIDB, where the changes in mean area under the time–plasma concentration curve (AUC) and maximum plasma concentration (C_max) values were calculated by the DIDB Editorial Team.