Contribution of Hepatic Organic Anion-Transporting Polypeptides to Docetaxel Uptake and Clearance

Lee, Hannah Hyejeong; Leake, Brenda F.; Teft, Wendy A.; Tirona, Rommel G.; Kim, Richard B.; Ho, Richard

doi:10.1158/1535-7163.mct-14-0547

Cited by 35 publications

(38 citation statements)

References 44 publications

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“…These findings have been independently verified (30)(31)(32)(33)(34), and are consistent with in vitro studies that have identified paclitaxel as a potent inhibitor of OATP1B1-(35, 36) and OATP1B3-mediated transport (35,37,38). However, none of the other known 9 human OATPs or other rodent OATPs are capable of transporting paclitaxel (39), and similar results have been obtained with docetaxel (40). These studies highlight the notion that OATPs capable of transporting paclitaxel need to be expressed in tissues such that the drug can exert cellular injury.…”

Section: Oatp1b2 As a Putative Paclitaxel Transporter In Mouse Neuronssupporting

confidence: 87%

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

Leblanc¹,

Sprowl²,

Alberti³

et al. 2018

Journal of Clinical Investigation

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Section: Oatp1b2 As a Putative Paclitaxel Transporter In Mouse Neuronssupporting

confidence: 87%

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

Leblanc¹,

Sprowl²,

Alberti³

et al. 2018

Journal of Clinical Investigation

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“…Consistent with its decreased membrane expression, the 521T>C SNP affected mainly the maximum transport velocity in comparison to substrate affinity . The deleterious functional consequence of the 521T>C variant was confirmed in subsequent studies with a diverse list of OATP1B1 substrates, including rifampin, pravastatin, atorvastatin, rosuvastatin, atrasentan, ezetimibe glucuronide, methotrexate and docetaxel . Another common variant associated with potentially altered transport activity of OATP1B1 is 388A>G (*1b), located in exon 4, but the functional consequences of this variant remain controversial.…”

Section: Slco1b1 Genetic Variabilitymentioning

confidence: 92%

Interindividual and interethnic variability in drug disposition: polymorphisms in organic anion transporting polypeptide 1B1 (OATP1B1; SLCO1B1)

Lee

2017

Brit J Clinical Pharma

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OATP1B1 (SLCO1B1) is predominantly expressed at the basolateral membrane of hepatocytes and is critically important for the hepatic uptake and clearance of numerous drug substrates and endogenous compounds. In general, the organic anion transporting polypeptides (OATP; SLCO) represent a superfamily of uptake transporters that mediate the sodium-independent transport of a diverse range of amphipathic organic compounds including bile salts, steroid conjugates, thyroid hormones, anionic peptides, numerous drugs and other xenobiotic substances. OATP1B1 is highly polymorphic and a number of relevant and ethnically dependent polymorphisms have been identified and functionally characterized. In particular, the SLCO1B1 521T>C and 388A>G polymorphisms are commonly occurring variants in ethnically diverse populations and numerous in vitro and clinical studies have evaluated the consequences of these variants to interindividual differences in drug disposition and response. OATP1B1 is particularly important for the disposition of HMG-CoA reductase inhibitors, or statins, as it is known to efficiently transport most statins to their site of action within hepatocytes. Many studies have focused on the consequences of OATP1B1 variants to statin disposition in vitro and in vivo and would suggest that genetic variability in SLCO1B1 has important implications for statin pharmacokinetics, risk for statin-induced myopathy, and modulation of statin treatment response. This review describes what is currently known regarding SLCO1B1 genotype, OATP1B1 protein expression and interindividual and interethnic consequences to drug disposition, with particular focus on statin pharmacokinetics and implications for drug response and toxicity.

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“…MDCKII cells stably expressing single (OATP1B1, OATP1B3 and MDR1) and double (OATP1B1/MDR1 and OATP1B3/MDR1) transporters, including control cells (MDCKII-Co), were generated and characterized previously (Lee et al, 2015). For this study, single (MDCKII-OATP1A2)-and double (MDCKII-OATP1A2/MDR1)transfected cells were also generated using the same methods as conducted previously (Lee et al, 2015). Briefly, both parent MDCKII cells and MDCKII-MDR1 cells were transfected or retransfected with the plasmids pcDNA3.1(1)/OATP1A2 using Lipofectamine 2000 reagent (Invitrogen) according to the manufacturer's instructions.…”

Section: Generation Of Stably Transfected Mdckii-oatp1a2 and Mdckii-omentioning

confidence: 99%

“…Protein expressions from MDCKII-OATP1A2 and -OATP1A2/MDR1 cells, including control cells, were examined by immunoblot analysis of plasma membrane enriched preparations. Crude cell membrane fractions were conducted as described previously with minor modification (Kim et al, 1998;Lee et al, 2015). Briefly, cells were scraped, collected, and homogenized in 5 mM Hepes (pH 7.2) cell lysis buffer containing 1Â protease inhibitor cocktails (Roche).…”

Section: Crude Cell Membrane Fractions and Immunoblot Analysismentioning

confidence: 99%

Contribution of Organic Anion-Transporting Polypeptides 1A/1B to Doxorubicin Uptake and Clearance

Lee¹,

Leake²,

Kim³

et al. 2016

Mol Pharmacol

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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.

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Contribution of Hepatic Organic Anion-Transporting Polypeptides to Docetaxel Uptake and Clearance

Cited by 35 publications

References 44 publications

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

Interindividual and interethnic variability in drug disposition: polymorphisms in organic anion transporting polypeptide 1B1 (OATP1B1; SLCO1B1)

Contribution of Organic Anion-Transporting Polypeptides 1A/1B to Doxorubicin Uptake and Clearance

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