Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline

Davenport, James M.; Covington, Paul S.; Bonifacio, Laura; McIntyre, Gail; Venitz, Jürgen

doi:10.1002/jcph.442

Cited by 39 publications

(67 citation statements)

References 25 publications

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“…The mechanism of these changes has not yet been fully worked out. It is worth noting that the clinical relevance of MRP2 inhibition DDI is minimal in humans, with exposure levels reaching 121%-234% of those in normal subjects, depending on the drug considered (Chester et al, 2003;Suwannakul et al, 2008;Ieiri et al, 2009;Brennan et al, 2015;Davenport et al, 2015). Recently, the specificity of CPs I and III transport was studied using cells transfected with various transporters (Bednarczyk and Boiselle, 2016).…”

Section: Coproporphyrin As Endogenous In Vivo Probe For Oatp1bmentioning

confidence: 99%

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

Shen

Dai

Liu

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

109

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Inhibition of organic anion-transporting polypeptide (OATP)1B function can lead to serious clinical drug-drug interactions, thus a thorough evaluation of the potential for this type of interaction must be completed during drug development. Therefore, sensitive and specific biomarkers for OATP function that could be used in conjunction with clinical studies are currently in demand. In the present study, preclinical evaluations were conducted to characterize the suitability of coproporphyrins (CPs) I and III as markers of hepatic OATP functional activity. Active uptake of CPs I and III was observed in human embryonic kidney (HEK) 293 cells singly expressing human OATP1B1 (hOATP1B1), hOATP1B3, cynomolgus monkey OATP1B1 (cOATP1B1), or cOATP1B3, as well as human and monkey hepatocytes. Cyclosporin A (100 mg/kg, oral) markedly increased the area under the curve (AUC) plasma concentrations of CPs I and III by 2.6-and 5.2-fold, while rifampicin (15 mg/kg, oral) increased the AUCs by 2.7-and 3.6-fold, respectively. As the systemic exposure increased, the excretion of both isomers in urine rose from 1.6-to 4.3-fold in monkeys. In agreement with this finding, the AUC of rosuvastatin (RSV) in cynomolgus monkeys increased when OATP1B inhibitors were coadministered. In Oatp1a/1b gene cluster knockout mice (Oatp1a/1b 2/2 ), CPs in plasma and urine were significantly increased compared with wild-type animals (7.1-to 18.4-fold; P , 0.001), which were also in agreement with the changes in plasma RSV exposure (14.6-fold increase). We conclude that CPs I and III in plasma and urine are novel endogenous biomarkers reflecting hepatic OATP function, and the measurements have the potential to be incorporated into the design of early clinical evaluation.

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Section: Coproporphyrin As Endogenous In Vivo Probe For Oatp1bmentioning

confidence: 99%

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

Shen

Dai

Liu

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

109

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“…Animal studies demonstrated that eluxadoline interacts with opioid receptors in the gut to reduce intestinal contractility and inhibit neurogenically mediated secretion, while normalizing stress-induced acceleration of upper GI transit, without rebound constipation [13,14]. The activity at the d-opioid receptor ameliorated the anti-transit effects of the l-opioid receptor activity [14].…”

Section: Pharmacodynamicsmentioning

confidence: 98%

“…Plasma protein binding of eluxadoline was 81 % [5]. The mechanism of eluxadoline metabolism is currently unclear; however, some evidence exists pointing to limited glucuronidation leading to the formation of an acyl glucuronide metabolite, detectable in urine [5,13]. Eluxadoline is mostly (82 %) excreted in feces; \1 % was found in the urine.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Eluxadoline is not associated with a clinically relevant prolongation of the QT interval at doses of 1000 mg (10 times the maximum recommended dose) [13].…”

Section: Pharmacodynamicsmentioning

confidence: 99%

“…Eluxadoline is a l-opioid receptor agonist [binding affinity (Ki) of 1.8 nmol/L for the human receptor], a d-opioid receptor antagonist (Ki of 430 nmol/L for the human receptor), and a j-opioid receptor agonist (Ki as yet unknown for the human receptor) [13]. Animal studies demonstrated that eluxadoline interacts with opioid receptors in the gut to reduce intestinal contractility and inhibit neurogenically mediated secretion, while normalizing stress-induced acceleration of upper GI transit, without rebound constipation [13,14].…”

Section: Pharmacodynamicsmentioning

confidence: 99%

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Eluxadoline: First Global Approval

Garnock-Jones

2015

Drugs

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Eluxadoline (Viberzi(™)), developed by Actavis (now Allergan), is an orally administered, first-in-class compound that functions as both a µ-opioid receptor agonist and a δ-opioid receptor antagonist, and is indicated for the treatment of diarrhoea-predominant irritable bowel syndrome (IBS-D) in adults. The agent was originally developed by Janssen Pharmaceutica. Eluxadoline has been approved in the US, and submissions to other global authorities are being contemplated or planned. This article summarizes the milestones in the development of eluxadoline leading to this first approval for IBS-D.

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Diarrhea-predominant irritable bowel syndrome: Diagnosis, etiology, and new treatment considerations

Lacy

Moreau

2016

Journal of the American Association of Nurse Practitioners

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Purpose To provide an overview of irritable bowel syndrome (IBS), specifically the efficacy and tolerability of treatment options for diarrhea‐predominant IBS (IBS‐D). Data sources Research articles available via PubMed were reviewed. Conclusions IBS is a chronic multifactorial disorder that has a negative impact on patient‐related quality of life. Genetic factors, psychosociologic factors, alterations in the gut microbiota, and changes in immune, motor, and sensory responses to various stimuli all may be involved in the development of IBS. While pharmacologic therapies for IBS‐D have historically been limited (e.g., alosetron), newer therapies (eluxadoline and rifaximin), both approved in the United States in 2015, may be considered for appropriate patients for the management of IBS‐D. Implications for practice Nurse practitioners play an important role in the diagnosis, care, and management of patients with IBS‐D. The goals of therapy should be to reach a correct diagnosis before initiating therapy, provide reassurance to the patient, educate the patient on potential treatment options, improve IBS‐D symptoms, minimize risk of harm with treatment, and maximize patient‐related quality of life. The authors present a treatment algorithm to guide nurse practitioners on the management of patients with IBS‐D.

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Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline

Cited by 39 publications

References 25 publications

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

Eluxadoline: First Global Approval

Diarrhea-predominant irritable bowel syndrome: Diagnosis, etiology, and new treatment considerations

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