Clinically Relevant OATP2B1 Inhibitors in Marketed Drug Space

Abstract

OATP2B1 is an intestinal and hepatic drug uptake transporter. Intestinal OATP2B1 has been elucidated as the mechanism of unexpected clinical drug−drug interactions (DDIs), where drug exposure was unexpectedly decreased with unchanged half-life. Hepatic OATP2B1 may be an understudied clinical DDI mechanism. The aim of the present work was to understand the prevalence of clinically relevant intestinal and hepatic OATP2B1 inhibitors in marketed drug space. HEK293 cells stably overexpressing human OATP2B1 or vector control were generated and cultured for 72 h in a 96-well format. OATP2B1-mediated uptake of dibromofluorescein (DBF) was found to be optimal at 10 μM concentration and 30 min incubation time. A total of 294 drugs (top 300 marketed drugs, excluding biologics and restricted drugs, supplemented with ∼100 small-molecule drugs) were screened for OATP2B1 inhibition at 10 μM. Drugs demonstrating ≥50% inhibition in this screen were advanced for IC 50 determination, which was extrapolated to clinical intestinal and hepatic OATP2B1 inhibition as per 2017 FDA DDI guidance. Of the 294 drugs screened, 67 elicited ≥50% inhibition of OATP2B1-mediated DBF uptake at 10 μM screening concentration. For the 67 drugs flagged in the singleconcentration inhibition screen, upon evaluation of a full concentration range, IC 50 values could be determined for 58 drugs. OATP2B1 IC 50 values established for these 58 drugs were extrapolated as potentially clinically relevant at the intestinal level for 38 orally administered drugs (I gut /IC 50 ≥ 10), and 17 were flagged as potential clinical inhibitors of hepatic OATP2B1 uptake (1 + I in,max,u /IC 50 ≥ 1.1). This analysis of 294 drugs demonstrated prevalence of clinically relevant intestinal and hepatic OATP2B1 inhibitors to be 13 and 6%, respectively. As OATP2B1-inhibitor drugs are not exceedingly rare, these results suggest that clinical OATP2B1 DDIs have been rarely observed because OATP2B1 is uncommonly the predominant determinant of drug disposition.

Food Additives as Inhibitors of Intestinal Drug Transporter OATP2B1

“…The transport affinity of both substrates was comparable with previously published data. [26][27][28] Figure 1. Concentration-dependent uptake of (A) dibromofluorescein (DBF) and (B) estrone sulfate into HEK293 cells expressing OATP2B1 (○) or control (□).…”

“…13 On the other hand, the lack of clinical OATP2B1-mediated drug-drug interactions can be considered rather surprising, as in vitro OATP2B1 inhibitors are not particularly rare among clinically used drugs. 28 The reason could be that OATP2B1 is not the predominant mechanism in drug absorption in vivo as other contributing pathways may exist. Other reasons could be that OATP2B1 has been understudied and more clinical interactions appear when systematic research becomes common.…”

Potential Risk of Food-Drug Interactions: Citrus Polymethoxyflavones and Flavanones as Inhibitors of the Organic Anion Transporting Polypeptides (OATP) 1B1, 1B3, and 2B1

“…Only recently has OATP2B1 been recognized as the primary intestinal isoform that can mediate intestinal absorption of drugs and drug-drug and food-drug interactions [19,20,22,34]. Moreover, it seems to be the main OATP isoform mediating interactions between citrus juices and drugs, which were originally attributed to OATP1A2 [19,22,23,[34][35][36].…”

Direct Automated MALDI Mass Spectrometry Analysis of Cellular Transporter Function: Inhibition of OATP2B1 Uptake by 294 Drugs

“…The deuterated internal standard D 4 -E3S ( m / z 354.1418) was purchased from Toronto Research Chemicals (Toronto, Canada), and erlotinib was purchased from LC Laboratories (Woburn, USA). A compound set of 294 substances, compiled from the top 300 prescribed drugs in the US, excluding biologics and restricted substances, and ∼100 literature small-molecule drugs known to have an interaction with the transporter OATP2B1, has been described elsewhere …”

“…Recently, we tested a set of 294 drugs comprising the top-marketed drugs of 2017 and other known OATP inhibitors in an established OATP2B1 fluorescence assay and identified 58 inhibitors. Out of those 58 in vitro inhibitors, 64% were potentially clinically relevant intestinal OATP2B1 inhibitors and 29% were potentially clinically relevant hepatic OATP2B1 inhibitors, suggesting OATP2B1 is an understudied clinical DDI mechanism …”