Modulation of OATP1B-Type Transporter Function Alters Cellular Uptake and Disposition of Platinum Chemotherapeutics

Lancaster, Cynthia S.; Sprowl, Jason A.; Walker, Aisha L.; Hu, Shuiying; Gibson, Alice A.; Sparreboom, Alex

doi:10.1158/1535-7163.mct-12-0926

Cited by 55 publications

(53 citation statements)

References 38 publications

(44 reference statements)

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“…Previous microarray analysis showed that expression of transporter genes in the kidneys of wild-type and Oatp1b Ϫ/Ϫ mice is similar with the exception of Slc14a2, which was increased in Oatp1b Ϫ/Ϫ mice (17). Because Slc14a2 transcript encodes urea transporter A (UTA), a protein that has been shown to mediate cellular entry of hydroxyurea (30), real-time analysis was conducted to evaluate the relative expression of this gene in wild-type and Oatp1b Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 94%

Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics

Walker

Lancaster

Finkelstein

et al. 2013

American Journal of Physiology-Cell Physiology

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Hydroxyurea is currently the only FDA-approved drug that ameliorates the pathophysiology of sickle cell anemia. Unfortunately, substantial interpatient variability in the pharmacokinetics (PK) of hydroxyurea may result in variation of the drug's efficacy. However, little is known about mechanisms that modulate hydroxyurea PK. Recent in vitro studies identifying hydroxyurea as a substrate for organic anion transporting polypeptide (OATP1B) transporters prompted the current investigation assessing the role of OATP1B transporters in modulating hydroxyurea PK. Using wild-type and Oatp1b knockout (Oatp1b(-/-)) mice, hydroxyurea PK was analyzed in vivo by measuring [(14)C]hydroxyurea distribution in plasma, kidney, liver, urine, or the exhaled (14)CO2 metabolite. Plasma levels were significantly reduced by 20% in Oatp1b(-/-) mice compared with wild-type (area under the curve of 38.64 or 48.45 μg·h(-1)·ml(-1), respectively) after oral administration, whereas no difference was observed between groups following intravenous administration. Accumulation in the kidney was significantly decreased by twofold in Oatp1b(-/-) mice (356.9 vs. 748.1 pmol/g), which correlated with a significant decrease in urinary excretion. Hydroxyurea accumulation in the liver was also decreased (136.6 vs. 107.3 pmol/g in wild-type or Oatp1b(-/-) mice, respectively) correlating with a decrease in exhaled (14)CO2. These findings illustrate that deficiency of Oatp1b transporters alters the absorption, distribution, and elimination of hydroxyurea thus providing the first in vivo evidence that cell membrane transporters may play a significant role in modulating hydroxyurea PK. Future studies to investigate other transporters and their role in hydroxyurea disposition are warranted for understanding the sources of variation in hydroxyurea's PK.

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Section: Discussionmentioning

confidence: 94%

Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics

Walker

Lancaster

Finkelstein

et al. 2013

American Journal of Physiology-Cell Physiology

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“…Although formal drug interaction studies have not been performed to date with nab-paclitaxel, our present findings strongly suggest that drug-drug interactions at the level of hepatocellular uptake mechanisms would be exacerbated with a formulation like nab-paclitaxel. Conversely, CrEL may act as a perpetrator in known pharmacokinetic interactions involving other OATP1B substrates co-administered with paclitaxel [reviewed in (4)], such as etoposide (43), docetaxel (44), oxaliplatin (45), and SN-38 (46). …”

Section: Discussionmentioning

confidence: 99%

Influence of Drug Formulation on OATP1B-Mediated Transport of Paclitaxel

Nieuweboer

Gui

et al. 2014

Cancer Research

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Purpose Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters prior to metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically-important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by the choice of drug delivery system. Experimental Design Transport of paclitaxel, docetaxel, and cabazitaxel was studied in vitro using various cell lines transfected with OATP1B1, OATP1B3, or the rodent equivalent Oatp1b2. Pharmacokinetic studies were done in wildtype and Oatp1b2-knockout mice in the presence or absence of polysorbate 80 (PS80) or Kolliphor EL (formerly Cremophor EL; CrEL). Results Paclitaxel and docetaxel, but not cabazitaxel, were transported substrates of OATP1B1, OATP1B3, and Oatp1b2, and these transport processes were strongly reduced in the presence of clinically-relevant concentrations of PS80 and CrEL. In the absence of solubilizers, deficiency of Oatp1b2 in mice was associated with a significantly decreased taxane clearance due to a liver distribution defect (P<0.00001), but these kinetic changes were masked in the presence of PS80 or CrEL (P>0.05). Conclusions Our findings confirm the importance of OATP1B-type transporters in the hepatic elimination of taxanes, and that this process can be inhibited by PS80 and CrEL. These results suggest that the likelihood of drug-drug interactions mediated by these transporters is strongly dependent on the selected taxane solubilizer.

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“…Thus, various family members of the ABC transporter family as well as SLC and solute carrier organic anion transporters are expressed in the lung (Bosquillon, 2010). The solute carrier organic anion transporter OATP1B3 is expressed in normal lung as well as in solid lung tumors, and was shown to correlate with disposition and toxicity of platinum cancer chemotherapy drugs (Lancaster et al, 2013).…”

Section: Pulmonary Metabolism Of Resveratrol: In Vitro and In Vivomentioning

confidence: 99%

“Target-Site” Drug Metabolism and Transport

et al. 2015

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The recent symposium on "Target-Site" Drug Metabolism and Transport that was sponsored by the American Society for Pharmacology and Experimental Therapeutics at the 2014 Experimental Biology meeting in San Diego is summarized in this report. Emerging evidence has demonstrated that drug-metabolizing enzyme and transporter activity at the site of therapeutic action can affect the efficacy, safety, and metabolic properties of a given drug, with potential outcomes including altered dosing regimens, stricter exclusion criteria, or even the failure of a new chemical entity in clinical trials. Drug metabolism within the brain, for example, can contribute to metabolic activation of therapeutic drugs such as codeine as well as the elimination of potential neurotoxins in the brain. Similarly, the activity of oxidative and conjugative drug-metabolizing enzymes in the lung can have an effect on the efficacy of compounds such as resveratrol. In addition to metabolism, the active transport of compounds into or away from the site of action can also influence the outcome of a given therapeutic regimen or disease progression. For example, organic anion transporter 3 is involved in the initiation of pancreatic b-cell dysfunction and may have a role in how uremic toxins enter pancreatic b-cells and ultimately contribute to the pathogenesis of gestational diabetes. Finally, it is likely that a combination of target-specific metabolism and cellular internalization may have a significant role in determining the pharmacokinetics and efficacy of antibody-drug conjugates, a finding which has resulted in the development of a host of new analytical methods that are now used for characterizing the metabolism and disposition of antibody-drug conjugates. Taken together, the research summarized herein can provide for an increased understanding of potential barriers to drug efficacy and allow for a more rational approach for developing safe and effective therapeutics.

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Modulation of OATP1B-Type Transporter Function Alters Cellular Uptake and Disposition of Platinum Chemotherapeutics

Cited by 55 publications

References 38 publications

Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics

Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics

Influence of Drug Formulation on OATP1B-Mediated Transport of Paclitaxel

“Target-Site” Drug Metabolism and Transport

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