Drug and Bile Acid Transporters in Rosuvastatin Hepatic Uptake: Function, Expression, and Pharmacogenetics

Ho, Richard; Tirona, Rommel G.; Leake, Brenda F.; Glaeser, Hartmut; Lee, Wooin; Lemke, Christopher J.; Wang, Yi; Kim, Richard B.

doi:10.1053/j.gastro.2006.02.034

Cited by 544 publications

(553 citation statements)

References 35 publications

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“…6A, bottom panel), dmd.aspetjournals.org similar amounts of FLAG antibody or normal mouse IgG were used for immunoprecipitation in PMA and DMSO (CTL) treated cells. Pilot experiments confirmed that the newly custom-generated OATP1B3 antibody specifically recognized OATP1B3 in the HEK-293-OATP1B3 stable cell line and in human hepatocytes at the same molecular weight as the previously published OATP1B3 antibody (Ho et al, 2006; data not shown).…”

Section: Methodssupporting

confidence: 70%

“…The proteins were then transferred to nitrocellulose membranes. Membranes were blocked at 4°C overnight in 5% milk or BSA-based membrane blocking solution (Life Technologies, Carlsbad, CA) in Tris-buffered saline with Tween (TBST), and probed with the following antibodies: rabbit polyclonal OATP1B3 antibody [provided by Dr. Richard B. Kim (Ho et al, 2006) in Fig. 3B, or custom-generated anti-OATP1B3 antibody (Fisher Scientific Company, LLC, Denver, CO) according to a previous publication (König et al, 2000a) in Fig.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Novel Mechanism of Impaired Function of Organic Anion-Transporting Polypeptide 1B3 in Human Hepatocytes: Post-Translational Regulation of OATP1B3 by Protein Kinase C Activation

et al. 2014

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The organic anion-transporting polypeptide (OATP) 1B3 is a membrane transport protein that mediates hepatic uptake of many drugs and endogenous compounds. Currently, determination of OATP-mediated drug-drug interactions in vitro is focused primarily on direct substrate inhibition. Indirect inhibition of OATP1B3 activity is under-appreciated. OATP1B3 has putative protein kinase C (PKC) phosphorylation sites. Studies were designed to determine the effect of PKC activation on OATP1B3-mediated transport in human hepatocytes using cholecystokinin-8 (CCK-8), a specific OATP1B3 substrate, as the probe. A PKC activator, phorbol-12-myristate-13-acetate (PMA), did not directly inhibit [ 3 H]CCK-8 accumulation in human sandwich-cultured hepatocytes (SCH). However, pretreatment with PMA for as little as 10 minutes rapidly decreased [ 3 H]CCK-8 accumulation. Treatment with a PKC inhibitor bisindolylmaleimide (BIM) I prior to PMA treatment blocked the inhibitory effect of PMA, indicating PKC activation is essential for downregulating OATP1B3 activity. PMA pretreatment did not affect OATP1B3 mRNA or total protein levels. To determine the mechanism(s) underlying the indirect inhibition of OATP1B3 activity upon PKC activation, adenoviral vectors expressing FLAG-Myc-tagged OATP1B3 (Ad-OATP1B3) were transduced into human hepatocytes; surface expression and phosphorylation of OATP1B3 were determined by biotinylation and by an anti-phosphor-Ser/Thr/Tyr antibody, respectively. PMA pretreatment markedly increased OATP1B3 phosphorylation without affecting surface or total OATP1B3 protein levels. In conclusion, PKC activation rapidly decreases OATP1B3 transport activity by posttranslational regulation of OATP1B3. These studies elucidate a novel indirect inhibitory mechanism affecting hepatic uptake mediated by OATP1B3, and provide new insights into predicting OATP-mediated drug interactions between OATP substrates and kinase modulator drugs/endogenous compounds.

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Section: Methodssupporting

confidence: 70%

Section: Methodsmentioning

confidence: 99%

Novel Mechanism of Impaired Function of Organic Anion-Transporting Polypeptide 1B3 in Human Hepatocytes: Post-Translational Regulation of OATP1B3 by Protein Kinase C Activation

et al. 2014

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“…Atorvastatin [164] 0.2 Atazanavir [165] 3.6 a Estriol [158] Benzylpenicillin [35] Atorvastatin [164] 0.7 Pregnenolone sulfate [158] Estrone [158] Bosentan [166] 202 Benzylpenicillin [36] 16 000 a Prostaglandin E2 [35] Pregnenolone sulfate [157,158] 3.5 a Fexofenadine [41] Cerivastatin [164] 66 a Taurocholate [41] 72 Testosterone [158] 15 a /21 a Fluvastatin [162,167] 0.7 Cimetidine [36] Glibenclamide [163] 6.3 Ciclosporin [154] 0.07 a Pitavastatin [161] 1.2 Darunavir [165] 26 a Pravastatin [37,41] 2250 Digoxin [164] Rosuvastatin [87,154] 2.4/6.4 Efavirenz [165] 9.6 a Tebipenem pivoxil [156] >1000 Gemfibrozil [154,162,164] 8 a Glibenclamide [164] Indinavir [168] 3.0 Indometacin [36,164] Lopinavir [165] 0.7 a Lovastatin [164] Memantine [164] Mifepristone [158] 2.2 a /4.7 a Nelfinavir [165] 0.9 a Pravastatin [36,37] 5 500 a /1 020 a Probenecid …”

Section: Oatp1a2 (Oatp-a)mentioning

confidence: 99%

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Grandvuinet

Vestergaard

Rapin³

et al. 2012

Journal of Pharmacy and Pharmacology

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Objectives This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in‐vitro methods presently employed in drug–drug interaction (DDI) investigations. Key findings Current knowledge on the intestinal expression of the apical sodium‐dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3‐5, the multidrug resistance associated proteins (MRP) 1–6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter α/β (OSTα/β) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in‐vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in‐vitro parameters for transporters (Km/Ki/IC50, efflux ratio). The applicability of using a cut‐off value (estimated based on the intestinal drug concentration divided by the Ki or IC50) has also been considered. Summary A re‐evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P‐glycoprotein. Moreover, the interplay between various processes that a drug is subject to in‐vivo such as translocation by several transporters and dissolution should be considered.

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“…In human hepatocytes, OATP1B1, OATP1B3, and OATP2B1 isoforms are expressed at the basolateral plasma membrane of hepatocytes. In addition to OATs and OATPs, human Na + -taurocholate co-transporting polypeptide (NTCP), which constitutes the main uptake system for bile acids, has been shown to also transport some drugs in a Na + -dependent manner (11). The uptake of 99m Tc-mebrofenin and ICG by any of these transporters is therefore probable.…”

Section: Introductionmentioning

confidence: 99%

Transporters involved in the hepatic uptake of 99mTc-mebrofenin and indocyanine green

Graaf

Häusler

Heger

et al. 2011

Journal of Hepatology

269

219

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The transporter specificity of (99m)Tc-mebrofenin and ICG partially overlaps as both compounds are transported by OATP1B3. (99m)Tc-mebrofenin is also taken up by OATP1B1, whereas ICG is additionally transported by NTCP. Accepted ManuscriptTransporters involved in the hepatic uptake of 99m Tc-mebrofenin and indocyanine green This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Drug and Bile Acid Transporters in Rosuvastatin Hepatic Uptake: Function, Expression, and Pharmacogenetics

Cited by 544 publications

References 35 publications

Novel Mechanism of Impaired Function of Organic Anion-Transporting Polypeptide 1B3 in Human Hepatocytes: Post-Translational Regulation of OATP1B3 by Protein Kinase C Activation

Novel Mechanism of Impaired Function of Organic Anion-Transporting Polypeptide 1B3 in Human Hepatocytes: Post-Translational Regulation of OATP1B3 by Protein Kinase C Activation

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Transporters involved in the hepatic uptake of 99mTc-mebrofenin and indocyanine green

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