Effect of OATP1B1 genotypes on plasma concentrations of endogenous OATP1B1 substrates and drugs, and their association in healthy volunteers

Mori, Daisuke; Kashihara, Yushi; Yoshikado, Takashi; Kimura, Miyuki; Hirota, Tomoyoshi; Matsuki, Shunji; Maeda, Kazuya; Irie, Shin; Ieiri, Ichiro; Sugiyama, Yuichi; Kusuhara, Hiroyuki

doi:10.1016/j.dmpk.2018.09.003

Cited by 55 publications

(75 citation statements)

References 36 publications

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“…Our second finding, that baseline levels of CP‐I but not CP‐III were associated with SLCO1B1 c.521T>C genotype, was somewhat surprising, and suggests that there may be quantitative differences in the influx pathways of the two metabolites. Recent study from Mori et al . also showed that CP‐I level was significantly associated with SLCO1B1 c.521T>C. Previously, we have shown that HDA and TDA are substrates of OATP1B1 and their levels are significantly higher in individuals who are carriers of c.521T>C .…”

Section: Discussionmentioning

confidence: 47%

Organic Anion Transporter Polypeptide 1B1 Polymorphism Modulates the Extent of Drug–Drug Interaction and Associated Biomarker Levels in Healthy Volunteers

Yee

Giacomini

Shen

et al. 2019

Clinical Translational Sci

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Understanding transporter‐mediated drug–drug interactions is an integral part of risk assessment in drug development. Recent studies support the use of hexadecanedioate (HDA), tetradecanedioate (TDA), coproporphyrin (CP)‐I, and CP‐III as clinical biomarkers for evaluating organic anion‐transporting polypeptide (OATP)1B1 (SLCO1B1) inhibition. The current study investigated the effect of OATP1B1 genotype c.521T>C (OATP1B1‐Val174Ala) on the extent of interaction between cyclosporin A (CsA) and pravastatin, and associated endogenous biomarkers of the transporter (HDA, TDA, CP‐I, and CP‐III), in 20 healthy volunteers. The results show that the levels of each clinical biomarker and pravastatin were significantly increased in plasma samples of the volunteers following administration of pravastatin plus CsA compared with pravastatin plus placebo. The overall fold change in the area under the concentration–time curve (AUC) and maximum plasma concentration (Cmax) was similar among the four biomarkers (1.8–2.5‐fold, paired t‐test P value < 0.05) in individuals who were homozygotes or heterozygotes of the major allele, c.521T. However, the fold change in AUC and Cmax for HDA and TDA was significantly abolished in the subjects who were c.521‐CC, whereas the respective fold change in AUC and Cmax for pravastatin and CP‐I and CP‐III were slightly weaker in individuals who were c.521‐CC compared with c.521‐TT/TC genotypes. In addition, this study provides the first evidence that SLCO1B1 c.521T>C genotype is significantly associated with CP‐I but not CP‐III levels. Overall, these results suggest that OATP1B1 genotype can modulate the effects of CsA on biomarker levels; the extent of modulation differs among the biomarkers.

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Section: Discussionmentioning

confidence: 47%

Organic Anion Transporter Polypeptide 1B1 Polymorphism Modulates the Extent of Drug–Drug Interaction and Associated Biomarker Levels in Healthy Volunteers

Yee

Giacomini

Shen

et al. 2019

Clinical Translational Sci

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“…Other compounds, except for GCDCA‐S, GDCA‐S, GCDCA‐G and GDCA‐G, in the plasma samples were analyzed using LC‐MS/MS. Plasma samples were prepared by protein precipitation as described previously . Chromatography was performed on a Prominence LC system, or Nexera X2 LC system (Shimadzu, Kyoto, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…[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. 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.…”

Section: Articlementioning

confidence: 95%

“…Plasma samples analyzed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) were prepared by protein precipitation as described previously. 17 Valsartan was analyzed on the same chromatographic condition (Supplemental Methods) using valsartan-d9 as internal standard. The multiple reaction monitoring precursor/product ion transitions are summarized in Supplemental Methods.…”

Section: Lc-ms/ms Analysis Of Drugsmentioning

confidence: 99%

“…Plasma samples were prepared by protein precipitation as described previously. 17 Chromatography was performed on a Prominence LC system, or Nexera X2 LC system (Shimadzu, Kyoto, Japan). Liquid chromatographic conditions were summarized in Supplemental Methods.…”

Section: Quantification Of Endogenous Substratesmentioning

confidence: 99%

See 2 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

Self Cite

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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Organic Anion Transporting Polypeptides Oatp

Tirona

Kim

2022

Drug Transporters

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Effect of OATP1B1 genotypes on plasma concentrations of endogenous OATP1B1 substrates and drugs, and their association in healthy volunteers

Cited by 55 publications

References 36 publications

Organic Anion Transporter Polypeptide 1B1 Polymorphism Modulates the Extent of Drug–Drug Interaction and Associated Biomarker Levels in Healthy Volunteers

Organic Anion Transporter Polypeptide 1B1 Polymorphism Modulates the Extent of Drug–Drug Interaction and Associated Biomarker Levels in Healthy Volunteers

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

Organic Anion Transporting Polypeptides Oatp

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