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Contribution of Organic Anion-Transporting Polypeptides 1A/1B to Doxorubicin Uptake and Clearance.
Lee HH, Leake BF, Kim RB, Ho RH
(2017) Mol Pharmacol 91: 14-24
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Animals, Biological Transport, Cell Membrane, Dogs, Doxorubicin, HeLa Cells, Humans, Kinetics, Liver, Liver-Specific Organic Anion Transporter 1, Madin Darby Canine Kidney Cells, Male, Mice, Models, Biological, Mutant Proteins, Organic Anion Transporters, Organic Anion Transporters, Sodium-Independent, Organic Cation Transport Proteins, Rats, Transfection
Show Abstract · Added November 10, 2016
The organic anion-transporting polypeptides represent an important family of drug uptake transporters that mediate the cellular uptake of a broad range of substrates including numerous drugs. Doxorubicin is a highly efficacious and well-established anthracycline chemotherapeutic agent commonly used in the treatment of a wide range of cancers. Although doxorubicin is a known substrate for efflux transporters such as P-glycoprotein (P-gp; MDR1, ABCB1), significantly less is known regarding its interactions with drug uptake transporters. Here, we investigated the role of organic anion transporting polypeptide (OATP) transporters to the disposition of doxorubicin. A recombinant vaccinia-based method for expressing uptake transporters in HeLa cells revealed that OATP1A2, but not OATP1B1 or OATP1B3, and the rat ortholog Oatp1a4 were capable of significant doxorubicin uptake. Interestingly, transwell assays using Madin-Darby canine kidney II cell line cells stably expressing specific uptake and/or efflux transporters revealed that OATP1B1, OATP1B3, and OATP1A2, either alone or in combination with MDR1, significantly transported doxorubicin. An assessment of polymorphisms in SLCO1A2 revealed that four variants were associated with significantly impaired doxorubicin transport in vitro. In vivo doxorubicin disposition studies revealed that doxorubicin plasma area under the curve was significantly higher (1.7-fold) in Slco1a/1b versus wild-type mice. The liver-to-plasma ratio of doxorubicin was significantly decreased (2.3-fold) in Slco1a/1b2 mice and clearance was reduced by 40% compared with wild-type mice, suggesting Oatp1b transporters are important for doxorubicin hepatic uptake. In conclusion, we demonstrate important roles for OATP1A/1B in transporter-mediated uptake and disposition of doxorubicin.
Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
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21 MeSH Terms
Estrogen and insulin transport through the blood-brain barrier.
May AA, Bedel ND, Shen L, Woods SC, Liu M
(2016) Physiol Behav 163: 312-321
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Animals, Blood Vessels, Blood-Brain Barrier, Body Weight, Brain, Dietary Fats, Estrogens, Female, Glucose Transporter Type 1, Insulin, Insulin Resistance, Male, Obesity, Ovariectomy, Rats, Rats, Long-Evans, Synaptophysin
Show Abstract · Added March 2, 2017
Obesity is associated with insulin resistance and reduced transport of insulin through the blood-brain barrier (BBB). Reversal of high-fat diet-induced obesity (HFD-DIO) by dietary intervention improves the transport of insulin through the BBB and the sensitivity of insulin in the brain. Although both insulin and estrogen (E2), when given alone, reduce food intake and body weight via the brain, E2 actually renders the brain relatively insensitive to insulin's catabolic action. The objective of these studies was to determine if E2 influences the ability of insulin to be transported into the brain, since the receptors for both E2 and insulin are found in BBB endothelial cells. E2 (acute or chronic) was systemically administered to ovariectomized (OVX) female rats and male rats fed a chow or a high-fat diet. Food intake, body weight and other metabolic parameters were assessed along with insulin entry into the cerebrospinal fluid (CSF). Acute E2 treatment in OVX female and male rats reduced body weight and food intake, and chronic E2 treatment prevented or partially reversed high-fat diet-induced obesity. However, none of these conditions increased insulin transport into the CNS; rather, chronic E2 treatment was associated less-effective insulin transport into the CNS relative to weight-matched controls. Thus, the reduction of brain insulin sensitivity by E2 is unlikely to be mediated by increasing the amount of insulin entering the CNS.
Copyright © 2016 Elsevier Inc. All rights reserved.
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18 MeSH Terms
Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance.
Lee HH, Leake BF, Teft W, Tirona RG, Kim RB, Ho RH
(2015) Mol Cancer Ther 14: 994-1003
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Animals, Antineoplastic Agents, Biological Transport, Cell Line, Tumor, Docetaxel, Humans, Liver, Liver-Specific Organic Anion Transporter 1, Male, Mice, Mice, Knockout, Organic Anion Transporters, Organic Anion Transporters, Sodium-Independent, Rats, Solute Carrier Organic Anion Transporter Family Member 1B3, Taxoids, Tubulin Modulators
Show Abstract · Added February 25, 2015
The antimicrotubular agent docetaxel is a widely used chemotherapeutic drug for the treatment of multiple solid tumors and is predominantly dependent on hepatic disposition. In this study, we evaluated drug uptake transporters capable of transporting radiolabeled docetaxel. By screening an array of drug uptake transporters in HeLa cells using a recombinant vaccinia-based method, five organic anion-transporting polypeptides (OATP) capable of docetaxel uptake were identified: OATP1A2, OATP1B1, OATP1B3, OATP1C1, and Oatp1b2. Kinetic analysis of docetaxel transport revealed similar kinetic parameters among hepatic OATP1B/1b transporters. An assessment of polymorphisms (SNPs) in SLCO1B1 and SLCO1B3 revealed that a number of OATP1B1 and OATP1B3 variants were associated with impaired docetaxel transport. A Transwell-based vectorial transport assay using MDCKII stable cells showed that docetaxel was transported significantly into the apical compartment of double-transfected (MDCKII-OATP1B1/MDR1 and MDCKII-OATP1B3/MDR1) cells compared with single-transfected (MDCKII-OATP1B1 and MDCKII-OATP1B3) cells (P < 0.05) or control (MDCKII-Co) cells (P < 0.001). In vivo docetaxel transport studies in Slco1b2(-/-) mice showed approximately >5.5-fold higher plasma concentrations (P < 0.01) and approximately 3-fold decreased liver-to-plasma ratio (P < 0.05) of docetaxel compared with wild-type (WT) mice. The plasma clearance of docetaxel in Slco1b2(-/-) mice was 83% lower than WT mice (P < 0.05). In conclusion, this study demonstrates the important roles of OATP1B transporters to the hepatic disposition and clearance of docetaxel, and supporting roles of these transporters for docetaxel pharmacokinetics.
©2015 American Association for Cancer Research.
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18 MeSH Terms
Genetic and non-genetic determinants of raltegravir penetration into cerebrospinal fluid: a single arm pharmacokinetic study.
Johnson DH, Sutherland D, Acosta EP, Erdem H, Richardson D, Haas DW
(2013) PLoS One 8: e82672
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1, Adult, Anti-HIV Agents, Blood-Brain Barrier, Female, Genetic Association Studies, Homozygote, Humans, Male, Middle Aged, Permeability, Polymorphism, Single Nucleotide, Pyrrolidinones, Raltegravir Potassium, Risk Factors
Show Abstract · Added March 13, 2015
BACKGROUND - Antiretroviral drugs vary in their central nervous system penetration, with better penetration possibly conferring neurocognitive benefit during human immunodeficiency virus (HIV) therapy. The efflux transporter gene ABCB1 is expressed in the blood-brain barrier, and an ABCB1 variant (3435C → T) has been reported to affect ABCB1 expression. The integrase inhibitor raltegravir is a substrate for ABCB1. We examined whether ABCB1 3435C → T affects raltegravir disposition into cerebrospinal fluid (CSF), and explored associations with polymorphisms in other membrane transporter genes expressed in the blood-brain barrier.
METHODS - Forty healthy, HIV-negative adults of European descent (20 homozygous for ABCB1 3435 C/C, 20 homozygous for 3435 T/T, each group divided equally between males and females) were given raltegravir 400 mg twice daily for 7 days. With the final dose, plasma was collected for pharmacokinetic analysis at 9 timepoints over 12 hours, and CSF collected 4 hours post dose.
RESULTS - The 4-hour CSF concentration correlated more strongly with 2-hour (r(2)=0.76, P=1.12 x 10(-11)) than 4-hour (r(2)=0.47, P=6.89 x 10(-6)) single timepoint plasma concentration, and correlated strongly with partial plasma area-under-the-curve values (AUC0-4h r(2)=0.86, P=5.15 x 10(-16)). There was no significant association between ABCB1 3435C → T and ratios of CSF-to-plasma AUC or concentration (p>0.05 for each comparison). In exploratory analyses, CSF-to-plasma ratios were not associated with 276 polymorphisms across 16 membrane transporter genes.
CONCLUSIONS - Among HIV-negative adults, CSF raltegravir concentrations do not differ by ABCB1 3435C → T genotype but strongly correlate with plasma exposure.
TRIAL REGISTRATION - ClinicalTrials.gov NCT00729924 http://clinicaltrials.gov/show/NCT00729924.
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16 MeSH Terms
7-Ketocholesterol induces P-glycoprotein through PI3K/mTOR signaling in hepatoma cells.
Wang SF, Chou YC, Mazumder N, Kao FJ, Nagy LD, Guengerich FP, Huang C, Lee HC, Lai PS, Ueng YF
(2013) Biochem Pharmacol 86: 548-60
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Acetylcysteine, Antibiotics, Antineoplastic, Antioxidants, Carcinoma, Hepatocellular, Cell Line, Cell Line, Tumor, Cell Survival, Cholesterol, Doxorubicin, Drug Resistance, Neoplasm, Hepatocytes, Humans, Hydroxycholesterols, Ketocholesterols, Lactic Acid, Oligomycins, Phosphatidylinositol 3-Kinases, Signal Transduction, TOR Serine-Threonine Kinases, Up-Regulation
Show Abstract · Added March 7, 2014
7-Ketocholesterol (7-KC) is found at an elevated level in patients with cancer and chronic liver disease. The up-regulation of an efflux pump, P-glycoprotein (P-gp) leads to drug resistance. To elucidate the effect of 7-KC on P-gp, P-gp function and expression were investigated in hepatoma cell lines Huh-7 and HepG2 and in primary hepatocyte-derived HuS-E/2 cells. At a subtoxic concentration, 48-h exposure to 7-KC reduced the intracellular accumulation and cytotoxicity of P-gp substrate doxorubicin in hepatoma cells, but not in HuS-E/2 cells. In Huh-7 cells, 7-KC elevated efflux function through the activation of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. 7-KC activated the downstream protein synthesis initiation factor 4E-BP1 and induced P-gp expression post-transcriptionally. The stimulation of efflux was reversible and could not be prevented by N-acetyl cysteine. Total cellular ATP content remained the same, whereas the lactate production was increased and fluorescence lifetime of protein-bound NADH was shortened. These changes suggested a metabolic shift to glycolysis, but glycolytic inhibitors did not eliminate 7-KC-mediated P-gp induction. These results demonstrate that 7-KC induces P-gp through PI3K/mTOR signaling and decreased the cell-killing efficacy of doxorubicin in hepatoma cells.
Copyright © 2013 Elsevier Inc. All rights reserved.
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1 Members
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21 MeSH Terms
On the origin of large flexibility of P-glycoprotein in the inward-facing state.
Wen PC, Verhalen B, Wilkens S, Mchaourab HS, Tajkhorshid E
(2013) J Biol Chem 288: 19211-20
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Adenosine Triphosphate, Animals, Biological Transport, Cell Membrane, Electron Spin Resonance Spectroscopy, Lipids, Mice, Molecular Dynamics Simulation, Protein Binding, Protein Structure, Tertiary, Substrate Specificity
Show Abstract · Added February 19, 2015
P-glycoprotein (Pgp) is one of the most biomedically relevant transporters in the ATP binding cassette (ABC) superfamily due to its involvement in developing multidrug resistance in cancer cells. Employing molecular dynamics simulations and double electron-electron resonance spectroscopy, we have investigated the structural dynamics of membrane-bound Pgp in the inward-facing state and found that Pgp adopts an unexpectedly wide range of conformations, highlighted by the degree of separation between the two nucleotide-binding domains (NBDs). The distance between the two NBDs in the equilibrium simulations covers a range of at least 20 Å, including, both, more open and more closed NBD configurations than the crystal structure. The double electron-electron resonance measurements on spin-labeled Pgp mutants also show wide distributions covering both longer and shorter distances than those observed in the crystal structure. Based on structural and sequence analyses, we propose that the transmembrane domains of Pgp might be more flexible than other structurally known ABC exporters. The structural flexibility of Pgp demonstrated here is not only in close agreement with, but also helps rationalize, the reported high NBD fluctuations in several ABC exporters and possibly represents a fundamental difference in the transport mechanism between ABC exporters and ABC importers. In addition, during the simulations we have captured partial entrance of a lipid molecule from the bilayer into the lumen of Pgp, reaching the putative drug binding site. The location of the protruding lipid suggests a putative pathway for direct drug recruitment from the membrane.
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12 MeSH Terms
miR-33 controls the expression of biliary transporters, and mediates statin- and diet-induced hepatotoxicity.
Allen RM, Marquart TJ, Albert CJ, Suchy FJ, Wang DQ, Ananthanarayanan M, Ford DA, Baldán A
(2012) EMBO Mol Med 4: 882-95
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 11, ATP-Binding Cassette Transporters, Adenosine Triphosphatases, Animals, Bile, Cells, Cultured, Diet, Gene Expression Regulation, Hepatocytes, Liver, Male, Mice, Mice, Inbred C57BL, MicroRNAs, Models, Biological, Phospholipid Transfer Proteins, Simvastatin
Show Abstract · Added February 12, 2016
Bile secretion is essential for whole body sterol homeostasis. Loss-of-function mutations in specific canalicular transporters in the hepatocyte disrupt bile flow and result in cholestasis. We show that two of these transporters, ABCB11 and ATP8B1, are functional targets of miR-33, a micro-RNA that is expressed from within an intron of SREBP-2. Consequently, manipulation of miR-33 levels in vivo with adenovirus or with antisense oligonucleotides results in changes in bile secretion and bile recovery from the gallbladder. Using radiolabelled cholesterol, we show that systemic silencing of miR-33 leads to increased sterols in bile and enhanced reverse cholesterol transport in vivo. Finally, we report that simvastatin causes, in a dose-dependent manner, profound hepatotoxicity and lethality in mice fed a lithogenic diet. These latter results are reminiscent of the recurrent cholestasis found in some patients prescribed statins. Importantly, pretreatment of mice with anti-miR-33 oligonucleotides rescues the hepatotoxic phenotype. Therefore, we conclude that miR-33 mediates some of the undesired, hepatotoxic effects of statins.
Copyright © 2012 EMBO Molecular Medicine.
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17 MeSH Terms
Predicting clopidogrel response using DNA samples linked to an electronic health record.
Delaney JT, Ramirez AH, Bowton E, Pulley JM, Basford MA, Schildcrout JS, Shi Y, Zink R, Oetjens M, Xu H, Cleator JH, Jahangir E, Ritchie MD, Masys DR, Roden DM, Crawford DC, Denny JC
(2012) Clin Pharmacol Ther 91: 257-63
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1, Aged, Aryl Hydrocarbon Hydroxylases, Aryldialkylphosphatase, Clopidogrel, Cytochrome P-450 CYP2C19, Databases, Nucleic Acid, Electronic Health Records, Female, Genotype, Humans, Male, Myocardial Infarction, Pharmacogenetics, Platelet Aggregation Inhibitors, Polymorphism, Genetic, Stents, Thrombosis, Ticlopidine, Treatment Outcome
Show Abstract · Added December 10, 2013
Variants in ABCB1 and CYP2C19 have been identified as predictors of cardiac events during clopidogrel therapy initiated after myocardial infarction (MI) or percutaneous coronary intervention (PCI). In addition, PON1 has recently been associated with stent thrombosis. The reported effects of these variants have not yet been replicated in a real-world setting. We used BioVU, the Vanderbilt DNA repository linked to de-identified electronic health records (EHRs), to find data on patients who were on clopidogrel treatment after an MI and/or a PCI; among these, we identified those who had experienced one or more recurrent cardiac events while on treatment (cases, n = 225) and those who had not experienced any cardiac event while on treatment (controls, n = 468). We found that CYP2C19*2 (hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.16-2.06, P = 0.003) and ABCB1 (HR 1.28, 95% CI 1.04-1.57, P = 0.018), but not PON1 (HR 0.91, 95% CI 0.73-1.12, P = 0.370), were associated with recurrent events. In this population, genetic signals for clopidogrel resistance in ABCB1 and CYP2C19 were replicated, supporting the use of EHRs for pharmacogenomic studies. Our data do not show an association between PON1 and recurrent cardiovascular events.
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5 Members
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21 MeSH Terms
The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients.
Birdwell KA, Grady B, Choi L, Xu H, Bian A, Denny JC, Jiang M, Vranic G, Basford M, Cowan JD, Richardson DM, Robinson MP, Ikizler TA, Ritchie MD, Stein CM, Haas DW
(2012) Pharmacogenet Genomics 22: 32-42
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1, Adult, Age Factors, Body Weight, Cytochrome P-450 CYP3A, Databases, Nucleic Acid, Dose-Response Relationship, Drug, Drug Monitoring, Electronic Health Records, Female, Genetic Association Studies, Genotype, Hemoglobins, Humans, Immunosuppressive Agents, Kidney Transplantation, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Pregnane X Receptor, Receptors, Steroid, Tacrolimus
Show Abstract · Added December 10, 2013
OBJECTIVE - Tacrolimus, an immunosuppressive drug widely prescribed in kidney transplantation, requires therapeutic drug monitoring due to its marked interindividual pharmacokinetic variability and narrow therapeutic index. Previous studies have established that CYP3A5 rs776746 is associated with tacrolimus clearance, blood concentration, and dose requirement. The importance of other drug absorption, distribution, metabolism, and elimination (ADME) gene variants has not been well characterized.
METHODS - We used novel DNA biobank and electronic medical record resources to identify ADME variants associated with tacrolimus dose requirement. Broad ADME genotyping was performed on 446 kidney transplant recipients, who had been dosed to a steady state with tacrolimus. The cohort was obtained from Vanderbilt's DNA biobank, BioVU, which contains linked deidentified electronic medical record data. Genotyping included Affymetrix drug-metabolizing enzymes and transporters Plus (1936 polymorphisms), custom Sequenom Massarray iPLEX Gold assay (95 polymorphisms), and ancestry-informative markers. The primary outcome was tacrolimus dose requirement defined as blood concentration to dose ratio.
RESULTS - In analyses, which adjusted for race and other clinical factors, we replicated the association of tacrolimus blood concentration to dose ratio with CYP3A5 rs776746 (P=7.15×10), and identified associations with nine variants in linkage disequilibrium with rs776746, including eight CYP3A4 variants. No NR1I2 variants were significantly associated. Age, weight, and hemoglobin were also significantly associated with the outcome. In final models, rs776746 explained 39% of variability in dose requirement and 46% was explained by the model containing clinical covariates.
CONCLUSION - This study highlights the utility of DNA biobanks and electronic medical records for tacrolimus pharmacogenomic research.
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6 Members
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24 MeSH Terms
Modulation of drug block of the cardiac potassium channel KCNA5 by the drug transporters OCTN1 and MDR1.
Yang T, McBride BF, Leake BF, Kim RB, Roden DM
(2010) Br J Pharmacol 161: 1023-33
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1, Animals, Anti-Arrhythmia Agents, Binding Sites, Biological Transport, CHO Cells, Cell Line, Cricetinae, Cricetulus, Gene Expression Regulation, Humans, Kv1.5 Potassium Channel, Organic Cation Transport Proteins, Protein Binding, Swine
Show Abstract · Added March 7, 2014
BACKGROUND AND PURPOSE - A common site for drug binding on voltage-gated ion channels is at the interior face of the channel pore. In this study, we tested the hypothesis that the extent of drug block of the human cardiac KCNA5 (K(v) 1.5) channel underlying the atrial-specific, ultra-rapidly activating, delayed K(+) current (I(Kur) ) is modulated by the drug uptake and efflux transporters encoded by organic cation transporter 1 (OCTN1) and multiple drug-resistant gene 1 (MDR1) and expressed in human heart.
EXPERIMENTAL APPROACH - Drug block of KCNA5 was assessed in Chinese hamster ovary cells transiently transfected with KCNA5 alone or in combination with the OCTN1 or MDR1 transporter construct, as well as in an MDR1 stably expressed cell line.
KEY RESULTS - Co-expression of OCTN1 significantly facilitated block by quinidine (10 µM), verapamil (20 µM), propafenone (5 µM) and clofilium (30 µM). Further evidence of drug transport modulating drug block was the finding that with OCTN1, block developed faster and only partially washed-out, and that block potentiation was prevented by cimetidine, an inhibitor of OCTN1. MDR1 expression attenuated KCNA5 block by erythromycin (an MDR1 substrate). Block was restored by reversin-205 (10 µM, an MDR1 inhibitor). MDR1 did not affect KCNA5 inhibition by KN-93 (1 µM), a blocker acting on the outer mouth of the channel pore.
CONCLUSIONS AND IMPLICATIONS - The extent of drug block of KCNA5 can be modulated by drug uptake and efflux transporters. These data provide further support for the idea that modifying intracellular drug concentrations could modulate the effects of blocking ion channels in patients.
© 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.
1 Communities
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16 MeSH Terms