Renal Excretion of Dabigatran: The Potential Role of Multidrug and Toxin Extrusion (MATE) Proteins

Shen, Hong; Yao, Ming; Sinz, Michael; Marathe, Punit; Rodrigues, A. David; Zhu, Mingshe

doi:10.1021/acs.molpharmaceut.9b00472

Cited by 10 publications

(11 citation statements)

References 58 publications

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“…Although administered as dabigatran etexilate, it is also important to know the mechanism of elimination for dabigatran, as it is dabigatran and not dabigatran etexilate concentrations that are assessed in plasma. Dabigatran is a substrate for the renal transporters, OCT2 [50], MATE1, and MATE2K [51]. Previous DDI studies have indicated that dabigatran etexilate (as measured by total plasma dabigatran, i.e.…”

Section: Dabigatran Etexilatementioning

confidence: 99%

Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug–Drug Interaction Studies

et al. 2020

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Understanding transporter-mediated drug-drug interactions (DDIs) for investigational agents is important during drug development to assess DDI liability, its clinical relevance, and to determine appropriate DDI management strategies. P-glycoprotein (P-gp) is an efflux transporter that influences the pharmacokinetics (PK) of various compounds. Assessing transporter induction in vitro is challenging and is not always predictive of in vivo effects, and hence there is a need to consider clinical DDI studies; however, there is no clear guidance on when clinical evaluation of transporter induction is required. Furthermore, there is no proposed list of index transporter inducers to be used in clinical studies. This review evaluated DDI studies with known P-gp inducers to better understand the mechanism and site of P-gp induction, as well as the magnitude of induction effect on the exposure of P-gp substrates. Our review indicates that P-gp and cytochrome P450 (CYP450) enzymes are coregulated via the pregnane xenobiotic receptor (PXR) and the constitutive androstane receptor (CAR). The magnitude of the decrease in substrate drug exposure by P-gp induction is generally less than that of CYP3A. Most P-gp inducers reduced total bioavailability with a minor impact on renal clearance, despite known expression of P-gp at the apical membrane of the kidney proximal tubules. Rifampin is the most potent P-gp inducer, resulting in an average reduction in substrate exposure ranging between 20 and 67%. For other inducers, the reduction in P-gp substrate exposure ranged from 12 to 42%. A lower reduction in exposure of the P-gp substrate was observed with a lower dose of the inducer and/or if the administration of the inducer and substrate was simultaneous, i.e. not staggered. These findings suggest that clinical evaluation of the impact of P-gp inducers on the PK of investigational agents that are substrates for P-gp might be warranted only for compounds with a relatively steep exposure-efficacy relationship.

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Section: Dabigatran Etexilatementioning

confidence: 99%

Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug–Drug Interaction Studies

et al. 2020

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“…A single dose of abrocitinib co‐administered with dabigatran etexilate (a sensitive P‐gp probe substrate and prodrug of active drug dabigatran) 25 increased plasma exposure of total dabigatran compared with dabigatran alone. MATE1 and MATE2K have been suggested to play important roles in the renal clearance of dabigatran 40 . Although in vitro results suggested potential MATE1 and MATE2K inhibition with abrocitinib, no clinical DDIs with the MATE1/2K substrate metformin were detected, indicating that the observed increase in dabigatran plasma exposure in vivo was primarily due to P‐gp inhibition.…”

Section: Discussionmentioning

confidence: 93%

“…MATE1 and MATE2K have been suggested to play important roles in the renal clearance of dabigatran. 40 Although in vitro results suggested potential MATE1 and MATE2K inhibition with abrocitinib, no clinical DDIs with the MATE1/2K substrate metformin were detected, indicating that the observed increase in dabigatran plasma exposure in vivo was primarily due to P-gp inhibition.…”

Section: Articlementioning

confidence: 94%

Evaluation of the Effect of Abrocitinib on Drug Transporters by Integrated Use of Probe Drugs and Endogenous Biomarkers

Vourvahis

Byon

Chang

et al. 2022

Clin Pharma and Therapeutics

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Abrocitinib is an oral Janus kinase 1 (JAK1) inhibitor currently approved in the United Kingdom for the treatment of moderate-to-severe atopic dermatitis (AD). As patients with AD may use medications to manage comorbidities, abrocitinib could be used concomitantly with hepatic and/or renal transporter substrates. Therefore, we assessed the potential effect of abrocitinib on probe drugs and endogenous biomarker substrates for the drug transporters of interest. In vitro studies indicated that, among the transporters tested, abrocitinib has the potential to inhibit the activities of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter 3 (OAT3), organic cation transporter 1 (OCT1), and multidrug and toxin extrusion protein 1 and 2K (MATE1/2K). Therefore, subsequent phase I, two-way crossover, open-label studies in healthy participants were performed to assess the impact of abrocitinib on the pharmacokinetics of the transporter probe substrates dabigatran etexilate (P-gp), rosuvastatin (BCRP and OAT3), and metformin (OCT2 and MATE1/2K), as well as endogenous biomarkers for MATE1/2K (N 1 -methylnicotinamide (NMN)) and OCT1 (isobutyryl-L -carnitine (IBC)). Co-administration with abrocitinib was shown to increase the plasma exposure of dabigatran by ~ 50%. In comparison, the plasma exposure and renal clearance of rosuvastatin and metformin were not altered with abrocitinib co-administration. Similarly, abrocitinib did not affect the exposure of NMN or IBC. An increase in dabigatran exposure suggests that abrocitinib inhibits P-gp activity. By contrast, a lack of impact on plasma exposure and/or renal clearance of rosuvastatin, metformin, NMN, or IBC suggests that BCRP, OAT3, OCT1, and MATE1/2K activity are unaffected by abrocitinib.

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“…The elimination of dabigatran (80% of dabigatran etexilate oral dose) is performed primarily via the kidneys probably by multidrug and toxin extrusion protein 1 (MATE1) and multidrug and toxin extrusion protein 2K (MATE2K), which could play an important role in its renal clearance and drug-drug or drug-food interactions. Dabigatran is a relatively poor P-gp substrate in the kidneys [18]. However, dabigatran etexilate (prodrug) could be subject to changes in absorption as it is a sub- Dabigatran etexilate is a prodrug, which is hydrolyzed to dabigatran after oral administration [10].…”

Section: Bioavailability and Metabolism Of Doacsmentioning

confidence: 99%

The Clinical Significance of Drug–Food Interactions of Direct Oral Anticoagulants

Grześk

Rogowicz

Wołowiec

et al. 2021

IJMS

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Cardiovascular diseases are the most common cause of death in the world. For almost 60 years, vitamin K antagonists (VKAs) were the mainstay of anticoagulation therapy, but in recent years direct oral anticoagulants (DOACs) have become the anticoagulant treatment of choice. DOACs were initially considered drugs with no significant food interactions; however, clinical observations from daily practice have proved otherwise as interactions with food ingredients have been reported. Food, dietary supplements or herbs may contain substances that, when administered concomitantly with DOACs, can potentially affect the plasma concentration of the drugs. The aim of this paper was to evaluate the clinical significance of drug–food interactions of DOACs, such as dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban. Patients treated with anticoagulants should avoid products containing St. John’s wort and take special care with other food ingredients. As the interest in dietary supplements is on the rise, healthcare providers can contribute to the development of well-designed clinical trials on interactions between DOACs and food, and distribute sufficient knowledge about the proper use of these supplements among patients.

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Renal Excretion of Dabigatran: The Potential Role of Multidrug and Toxin Extrusion (MATE) Proteins

Cited by 10 publications

References 58 publications

Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug–Drug Interaction Studies

Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug–Drug Interaction Studies

Evaluation of the Effect of Abrocitinib on Drug Transporters by Integrated Use of Probe Drugs and Endogenous Biomarkers

The Clinical Significance of Drug–Food Interactions of Direct Oral Anticoagulants

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