Comprehensive Evaluation of the Utility of 20 Endogenous Molecules as Biomarkers of OATP1B Inhibition Compared with Rosuvastatin and Coproporphyrin I

Barnett, S.; Ogungbenro, Kayode; Ménochet, Karelle; Shen, Hong; Humphreys, Griffith W; Galetin, Aleksandra

doi:10.1124/jpet.118.253062

Cited by 38 publications

(58 citation statements)

References 37 publications

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Section: Discussionmentioning

confidence: 99%

“…Comprehensive studies have been conducted to identify OATP1B endogenous biomarkers; however, most have deployed a limited rifampicin dose range, number of probe drugs, or number of endogenous compounds. 10,16 Here, we assessed the impact of OATP1B inhibition on endogenous biomarkers and probe drugs by a broader rifampicin dose range (150, 300, and 600 mg), eliciting weak to strong inhibition of OATP1B. In addition to the previously measured endogenous compounds, we also specifically measured bile acid sulfates, and two novel bile acid glucuronides as OATP1B biomarker candidates (GCDCA-G and GDCA-G).…”

Section: Discussionmentioning

confidence: 99%

“…We and other groups have demonstrated significant increases in the plasma concentrations of endogenous substrates such as bilirubins, coproporphyrins, amidated and nonamidated bile acids (including glucuronide and sulfate conjugates), and dicarboxylates following a single dose of cyclosporine A, rifampicin, and selected NCEs with OATP1B inhibition potential. [10][11][12][13][14][15][16] Furthermore, the plasma concentrations of some of these endogenous substrates were associated with SLCO1B1 genotype, as those of the statins were. 13,14,17 These cumulative data indicate that endogenous substrates could be used to support OATP1B subject phenotyping and DDI risk assessment.…”

Section: Articlementioning

confidence: 96%

“…As a result, various investigators have studied endogenous substrates following a single dose of cyclosporin A (100 mg) or rifampicin (600 mg); comparisons have been made to various statin probe drugs, such as rosuvastatin. 10,11,14,18 However, there are only few reports describing the dose-dependent effects of an OATP1B inhibitor, such as rifampicin. For example, the AUC ratio (rifampicin vs. placebo, AUCR) of total bilirubins was similar at a rifampicin dose of 300 and 600 mg, whereas the AUCR of coproporphyrin I (CP-I), direct bilirubins (D-BIL), and glycochenodeoxycholate-3-sulfate (GCDCA-S), as well as atorvastatin, was dose dependent.…”

Section: Articlementioning

confidence: 99%

“…These cumulative data indicate that endogenous substrates could be used to support OATP1B subject phenotyping and DDI risk assessment. As a result, various investigators have studied endogenous substrates following a single dose of cyclosporin A (100 mg) or rifampicin (600 mg); comparisons have been made to various statin probe drugs, such as rosuvastatin . However, there are only few reports describing the dose‐dependent effects of an OATP1B inhibitor, such as rifampicin.…”

mentioning

confidence: 99%

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Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs

Mori

Kimoto

Rago

et al. 2020

Clin Pharma and Therapeutics

137

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To address the most appropriate endogenous biomarker for drug–drug interaction risk assessment, eight healthy subjects received an organic anion transporting polypeptide 1B (OATP1B) inhibitor (rifampicin, 150, 300, and 600 mg), and a probe drug cocktail (atorvastatin, pitavastatin, rosuvastatin, and valsartan). In addition to coproporphyrin I, a widely studied OATP1B biomarker, we identified at least 4 out of 28 compounds (direct bilirubin, glycochenodeoxycholate‐3‐glucuronide, glycochenodeoxycholate‐3‐sulfate, and hexadecanedioate) that presented good sensitivity and dynamic range in terms of the rifampicin dose‐dependent change in area under the plasma concentration‐time curve ratio (AUCR). Their suitability as OATP1B biomarkers was also supported by the good correlation of AUC0‐24h between the endogenous compounds and the probe drugs, and by nonlinear regression analysis (AUCR−1 vs. rifampicin plasma Cmax (maximum total concentration in plasma)) to yield an estimate of the inhibition constant of rifampicin. These endogenous substrates can complement existing OATP1B‐mediated drug–drug interaction risk assessment approaches based on agency guidelines in early clinical trials.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Articlementioning

confidence: 96%

Section: Articlementioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs

Mori

Kimoto

Rago

et al. 2020

Clin Pharma and Therapeutics

137

View full text Add to dashboard Cite

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In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

Lu¹,

2020

Biopharm & Drug Disp

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Drug-drug interactions (DDIs) caused by the co-administration of multiple drugs are major safety concerns in the clinic. Several drugs have been withdrawn from the market due to perpetrator or victim DDIs. Strategies have been developed to assess DDI risks early in drug discovery to reduce DDI liabilities. High-to-medium throughput assays are available to identify undesirable scaffolds and to guide structural modifications to minimize DDIs. Definitive methods are used at later stages of drug discovery and development to provide a more accurate measurement of DDI parameters and to enable clinical translations. Physiologically based pharmacokinetic modeling and simulations are powerful tools to accurately predict DDIs and to assess risks in the clinic. Although significant advances have been made over the years, many challenges remain for clinical DDI translations. This includes DDIs involving non-cytochrome P450 enzymes, transporters, enzyme-transporter interplay, indirect effects from biologics, and pharmacodynamic based DDI. This review focuses on methods that are used to assess hepatic DDIs caused by enzyme inhibition and induction.

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Hepatic transporter‐mediated pharmacokinetic drug–drug interactions: Recent studies and regulatory recommendations

Izat

Şahin

2021

Biopharm & Drug Disp

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Transporter‐mediated drug–drug interactions are one of the major mechanisms in pharmacokinetic‐based drug interactions and correspondingly affecting drugs' safety and efficacy. Regulatory bodies underlined the importance of the evaluation of transporter‐mediated interactions as a part of the drug development process. The liver is responsible for the elimination of a wide range of endogenous and exogenous compounds via metabolism and biliary excretion. Therefore, hepatic uptake transporters, expressed on the sinusoidal membranes of hepatocytes, and efflux transporters mediating the transport from hepatocytes to the bile are determinant factors for pharmacokinetics of drugs, and hence, drug–drug interactions. In parallel with the growing research interest in this area, regulatory guidances have been updated with detailed assay models and criteria. According to well‐established preclinical results, observed or expected hepatic transporter‐mediated drug–drug interactions can be taken into account for clinical studies. In this paper, various methods including in vitro, in situ, in vivo, in silico approaches, and combinational concepts and several clinical studies on the assessment of transporter‐mediated drug–drug interactions were reviewed. Informative and effective evaluation by preclinical tools together with the integration of pharmacokinetic modeling and simulation can reduce unexpected clinical outcomes and enhance the success rate in drug development.

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Comprehensive Evaluation of the Utility of 20 Endogenous Molecules as Biomarkers of OATP1B Inhibition Compared with Rosuvastatin and Coproporphyrin I

Cited by 38 publications

References 37 publications

Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs

Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

Hepatic transporter‐mediated pharmacokinetic drug–drug interactions: Recent studies and regulatory recommendations

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