Impact of Hepatic Uptake Transporters on Pharmacokinetics and Drug−Drug Interactions: Use of Assays and Models for Decision Making in the Pharmaceutical Industry

The bile acid analogue [18F]LCATD (LithoCholic Acid Triazole Derivative) is transported in vitro by hepatic uptake transporters such as OATP1B1 and NTCP and efflux transporter BSEP. In this in vivo “proof of principle” study, we tested if [18F]LCATD may be used to evaluate drug-drug interactions (DDIs) caused by inhibition of liver transporters. Hepatic clearance of [18F]LCATD in rats was significantly modified upon coadministration of rifamycin SV or sodium fusidate, which are known to inhibit clinically relevant uptake transporters (OATP1B1, NTCP) and canalicular hepatic transporters (BSEP) in humans. Treatment with rifamycin SV (total dose 62.5 mg·Kg−1) reduced the maximum radioactivity of [18F]LCATD recorded in the liver from 14.2 ± 0.8% to 10.2 ± 0.9% and delayed t_max by 90 seconds relative to control rats. AUCliver 0–5 min, AUCbile 0–10 min and hepatic uptake clearance CLuptake,in vivo of rifamycin SV treated rats were significantly reduced, whereas AUCliver 0–30 min was higher than in control rats. Administration of sodium fusidate (30 mg·Kg−1) inhibited the liver uptake of [18F]LCATD, although to a lesser extent, reducing the maximum radioactivity in the liver to 11.5 ± 0.3%. These preliminary results indicate that [18F]LCATD may be a good candidate for future applications as an investigational tracer to evaluate altered hepatobiliary excretion as a result of drug-induced inhibition of hepatic transporters.

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Raltegravir Has a Low Propensity To Cause Clinical Drug Interactions through Inhibition of Major Drug Transporters: anIn VitroEvaluation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02049-13 ◽

2013 ◽

Vol 58 (3) ◽

pp. 1294-1301 ◽

Cited By ~ 14

Author(s):

Matthew L. Rizk ◽

Robert Houle ◽

Grace Hoyee Chan ◽

Mike Hafey ◽

Elizabeth G. Rhee ◽

...

Keyword(s):

Drug Interactions ◽

Organic Cation ◽

Drug Transporters ◽

Organic Anion ◽

Organic Cation Transporter ◽

Hepatic Uptake ◽

Efflux Transporters ◽

Renal Uptake ◽

No Inhibition ◽

Uptake Transporters

ABSTRACTRaltegravir (RAL) is a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor approved to treat HIV infection in adults in combination with other antiretrovirals. The potential of RAL to cause transporter-related drug-drug interactions (DDIs) as an inhibitor has not been well described to date. In this study, a series ofin vitroexperiments were conducted to assess the inhibitory effects of RAL on major human drug transporters known to be involved in clinically relevant drug interactions, including hepatic and renal uptake transporters and efflux transporters. For hepatic uptake transporters, RAL showed no inhibition of organic anion-transporting polypeptide 1B1 (OATP1B1), weak inhibition of OATP1B3 (40% inhibition at 100 μM), and no inhibition of organic cation transporter 1 (OCT1). Studies of renal uptake transporters showed that RAL inhibited organic anion transporters 1 and 3 (OAT1 and OAT3) with 50% inhibitory concentrations (IC50s) (108 μM and 18.8 μM, respectively) well above the maximum concentration of drug in plasma (Cmax) at the clinical 400-mg dose and did not inhibit organic cation transporter 2 (OCT2). As for efflux transporters, RAL did not inhibit breast cancer resistance protein (BCRP) and showed weak inhibition of multidrug and toxin extrusion protein 1 (MATE1) (52% inhibition at 100 μM) and MATE2-K (29% inhibition at 100 μM). These studies indicate that at clinically relevant exposures, RAL does not inhibit or only weakly inhibits hepatic uptake transporters OATP1B1, OATP1B3, and OCT1, renal uptake transporters OCT2, OAT1, and OAT3, as well as efflux transporters BCRP, MATE1, and MATE2-K. The propensity for RAL to cause DDIs via inhibition of these transporters is therefore considered low.

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In Vitro Characterization of Axitinib Interactions with Human Efflux and Hepatic Uptake Transporters: Implications for Disposition and Drug Interactions

Drug Metabolism and Disposition ◽

10.1124/dmd.113.051193 ◽

2013 ◽

Vol 41 (8) ◽

pp. 1575-1583 ◽

Cited By ~ 29

Author(s):

Eric L. Reyner ◽

Samantha Sevidal ◽

Mark A. West ◽

Andrea Clouser-Roche ◽

Sascha Freiwald ◽

...

Keyword(s):

Drug Interactions ◽

Hepatic Uptake ◽

In Vitro Characterization ◽

Uptake Transporters

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Model-based approaches to predict drug–drug interactions associated with hepatic uptake transporters: preclinical, clinical and beyond

Expert Opinion on Drug Metabolism & Toxicology ◽

10.1517/17425255.2013.759210 ◽

2013 ◽

Vol 9 (4) ◽

pp. 459-472 ◽

Cited By ~ 48

Author(s):

Hugh A Barton ◽

Yurong Lai ◽

Theunis C Goosen ◽

Hannah M Jones ◽

Ayman F El-Kattan ◽

...

Keyword(s):

Drug Interactions ◽

Hepatic Uptake ◽

Model Based ◽

Uptake Transporters

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Role of OATP1B1 and OATP1B3 in Drug-Drug Interactions Mediated by Tyrosine Kinase Inhibitors

Pharmaceutics ◽

10.3390/pharmaceutics12090856 ◽

2020 ◽

Vol 12 (9) ◽

pp. 856

Author(s):

Dominique A. Garrison ◽

Zahra Talebi ◽

Eric D. Eisenmann ◽

Alex Sparreboom ◽

Sharyn D. Baker

Keyword(s):

Tyrosine Kinase ◽

Drug Interactions ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Hepatic Uptake ◽

Medical Intervention ◽

Chemotherapeutic Agents ◽

Comprehensive Overview ◽

Regulatory Documents ◽

Uptake Transporters

Failure to recognize important features of a drug’s pharmacokinetic characteristics is a key cause of inappropriate dose and schedule selection, and can lead to reduced efficacy and increased rate of adverse drug reactions requiring medical intervention. As oral chemotherapeutic agents, tyrosine kinase inhibitors (TKIs) are particularly prone to cause drug-drug interactions as many drugs in this class are known or suspected to potently inhibit the hepatic uptake transporters OATP1B1 and OATP1B3. In this article, we provide a comprehensive overview of the published literature and publicly-available regulatory documents in this rapidly emerging field. Our findings indicate that, while many TKIs can potentially inhibit the function of OATP1B1 and/or OATP1B3 and cause clinically-relevant drug-drug interactions, there are many inconsistencies between regulatory documents and the published literature. Potential explanations for these discrepant observations are provided in order to assist prescribing clinicians in designing safe and effective polypharmacy regimens, and to provide researchers with insights into refining experimental strategies to further predict and define the translational significance of TKI-mediated drug-drug interactions.

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Everolimus drug interactions: application of a classification system for clinical decision making

Biopharmaceutics & Drug Disposition ◽

10.1002/bdd.524 ◽

2006 ◽

Vol 27 (9) ◽

pp. 421-426 ◽

Cited By ~ 36

Author(s):

John M. Kovarik ◽

Doris Beyer ◽

Robert L. Schmouder

Keyword(s):

Decision Making ◽

Drug Interactions ◽

Classification System ◽

Clinical Decision Making ◽

Clinical Decision

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Characterization of GCDC transport by human hepatic uptake transporters for in vitro testing purposes

Drug Metabolism and Pharmacokinetics ◽

10.1016/j.dmpk.2018.09.260 ◽

2019 ◽

Vol 34 (1) ◽

pp. S77

Author(s):

Beata Toth ◽

Zoltan Timar ◽

Viktoria Velky ◽

Zsuzsanna Gaborik ◽

Emese Kis ◽

...

Keyword(s):

Hepatic Uptake ◽

In Vitro Testing ◽

Uptake Transporters

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Bile Acid Uptake Transporters as Targets for Therapy

Digestive Diseases ◽

10.1159/000450983 ◽

2017 ◽

Vol 35 (3) ◽

pp. 251-258 ◽

Cited By ~ 27

Author(s):

Davor Slijepcevic ◽

Stan F.J. van de Graaf

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Energy Homeostasis ◽

Sodium Taurocholate ◽

Hepatic Uptake ◽

Farnesoid X Receptor ◽

Acid Uptake ◽

Bile Acid Uptake ◽

Uptake Transporters ◽

Conjugated Bile Acids

Background: Bile acids are potent signaling molecules that regulate glucose, lipid and energy homeostasis predominantly via the bile acid receptors farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor 5 (TGR5). The sodium taurocholate cotransporting polypeptide (NTCP) and the apical sodium dependent bile acid transporter (ASBT) ensure an effective circulation of (conjugated) bile acids. The modulation of these transport proteins affects bile acid localization, dynamics and signaling. The NTCP-specific pharmacological inhibitor myrcludex B inhibits hepatic uptake of conjugated bile acids. Multiple ASBT-inhibitors are already in clinical trials to inhibit intestinal bile acid uptake. Here, we discuss current insights into the consequences of targeting bile acid uptake transporters on systemic and intestinal bile acid dynamics and discuss the possible therapeutic applications that evolve as a result.

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