Anti-HIV and Anti-Hepatitis C Virus Drugs Inhibit P-Glycoprotein Efflux Activity in Caco-2 Cells and Precision-Cut Rat and Human Intestinal Slices

Abstract

P-glycoprotein (ABCB1), an ATP-binding-cassette efflux transporter, limits intestinal absorption of its substrates and is a common site of drug-drug interactions (DDIs). ABCB1 has been suggested to interact with many antivirals used to treat HIV and/or chronic hepatitis C virus (HCV) infections. Using bidirectional transport experiments in Caco-2 cells and a recently established ex vivo model of accumulation in precision-cut intestinal slices (PCIS) prepared from rat ileum or human jejunum, we evaluated the potential of anti-HIV and anti-HCV antivirals to inhibit intestinal ABCB1. Lopinavir, ritonavir, saquinavir, atazanavir, maraviroc, ledipasvir, and daclatasvir inhibited the efflux of a model ABCB1 substrate, rhodamine 123 (RHD123), in Caco-2 cells and rat-derived PCIS. Lopinavir, ritonavir, saquinavir, and atazanavir also significantly inhibited RHD123 efflux in human-derived PCIS, while possible interindividual variability was observed in the inhibition of intestinal ABCB1 by maraviroc, ledipasvir, and daclatasvir. Abacavir, zidovudine, tenofovir disoproxil fumarate, etravirine, and rilpivirine did not inhibit intestinal ABCB1. In conclusion, using recently established ex vivo methods for measuring drug accumulation in rat- and human-derived PCIS, we have demonstrated that some antivirals have a high potential for DDIs on intestinal ABCB1. Our data help clarify the molecular mechanisms responsible for reported increases in the bioavailability of ABCB1 substrates, including antivirals and drugs prescribed to treat comorbidity. These results could help guide the selection of combination pharmacotherapies and/or suitable dosing schemes for patients infected with HIV and/or HCV.

Interactions of Potential Anti-COVID-19 Compounds with Multispecific ABC and OATP Drug Transporters

“…Therefore, it may cause serious drug–drug interactions. Ritonavir and lopinavir are inhibitors of ABC multidrug transporters [ 21 , 22 ], both in vitro and in vivo [ 23 ], and according to studies with labeled ritonavir and lopinavir, these agents are transported substrates of ABCB1/Pgp [ 24 , 25 ], but not of ABCG2/BCRP [ 26 , 27 ].…”

Rifampicin Induces Gene, Protein, and Activity of P-Glycoprotein (ABCB1) in Human Precision-Cut Intestinal Slices

“…Tests to assess drug-mediated inhibition of intestinal ABCB1 have been established ( Guo et al, 2018 ; Martinec et al, 2019 ), but it does not hold true for induction ( Elmeliegy et al, 2020 ; FDA, 2020 ). Due to limitations of available methods, the FDA currently does not recommend a specific in vitro approach for testing investigational drugs’ induction effects on transporters ( FDA, 2020 ).…”

Determination of Antiviral Drugs and Their Metabolites Using Micro-Solid Phase Extraction and UHPLC-MS/MS in Reversed-Phase and Hydrophilic Interaction Chromatography Modes

“…Moreover, combination therapy using several antivirals from different classes with different mechanisms of action and therapy optimization are common in complex HIV treatment and in some cases of HCV treatment [ 9 ]. Anti-HIV and anti-HCV drugs are the typical examples of drugs administered orally where a high risk of DDI on intestinal efflux transporters can be expected [ 10 ]. Regulatory authorities as FDA and European Medicines Agency (EMA) are aware of this risk.…”

“…Therefore, they recommend cell line-based assays (e.g., Caco-2, MDCK) to reveal the DDI in preclinical research [ 11 , 12 ]. New, more complex promising models as precision-cut intestinal slices (PCIS) are also emerging in this process [ 10 ]. As anti-HIV and anti-HCV drugs are administered in combination therapy, preclinical research methods must be complex enough to reveal the majority of possible DDI in different experimental models.…”