scholarly journals Organic Anion-Transporting Polypeptide Genes Are Not Induced by the Pregnane X Receptor Activator Rifampin: Studies in Hepatocytes In Vitro and in Monkeys In Vivo

2019 ◽  
Vol 47 (12) ◽  
pp. 1433-1442 ◽  
Author(s):  
Congrong Niu ◽  
Yujin Wang ◽  
Xiaofeng Zhao ◽  
Sam Tep ◽  
Eisuke Murakami ◽  
...  
Keyword(s):  
Organic Anion ◽  
Pregnane X Receptor ◽  
Organic Anion Transporting Polypeptide ◽  
Receptor Activator

Substrate specificities of rat oatp1 and ntcp: implications for hepatic organic anion uptake

2003 ◽  
Vol 285 (5) ◽  
pp. G829-G839 ◽  
Author(s):  
Soichiro Hata ◽  
Pijun Wang ◽  
Nicole Eftychiou ◽  
Meenakshisundaram Ananthanarayanan ◽  
Ashok Batta ◽  
...  
Keyword(s):  
Bile Acids ◽  
Competitive Inhibition ◽  
Organic Anion ◽  
Inducible Promoter ◽  
Hydroxyl Groups ◽  
Organic Anion Transporting Polypeptide ◽  
Hela Cell Lines ◽  
Dependent Transport

Transport of a series of3H-radiolabeled C23, C24, and C27bile acid derivatives was compared and contrasted in HeLa cell lines stably transfected with rat Na+/taurocholate cotransporting polypeptide (ntcp) or organic anion transporting polypeptide 1 (oatp1) in which expression was under regulation of a zinc-inducible promoter. Similar uptake patterns were observed for both ntcp and oatp1, except that unconjugated hyodeoxycholate was a substrate of oatp1 but not ntcp. Conjugated bile acids were transported better than nonconjugated bile acids, and the configuration of the hydroxyl groups (α or β) had little influence on uptake. Although cholic and 23 norcholic acids were transported by ntcp and oatp1, other unconjugated bile acids (chenodeoxycholic, ursodeoxycholic) were not. In contrast to ntcp, oatp1-mediated uptake of the trihydroxy bile acids taurocholate and glycocholate was four- to eightfold below that of the corresponding dihydroxy conjugates. Ntcp mediated high affinity, sodium-dependent transport of [35S]sulfobromophthalein with a Kmsimilar to that of oatp1-mediated transport of [35S]sulfobromophthalein ( Km= 3.7 vs. 3.3 μM, respectively). In addition, for both transporters, uptake of sulfobromophthalein and taurocholic acid showed mutual competitive inhibition. These results indicate that the substrate specificity of ntcp is considerably broader than previously suspected and caution the extrapolation of transport data obtained in vitro to physiological function in vivo.

scholarly journals Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics

2013 ◽  
Vol 305 (12) ◽  
pp. C1223-C1229 ◽  
Author(s):  
Aisha L. Walker ◽  
Cynthia S. Lancaster ◽  
David Finkelstein ◽  
Russell E. Ware ◽  
Alex Sparreboom
Keyword(s):  
Organic Anion ◽  
Area Under The Curve ◽  
Wild Type ◽  
Organic Anion Transporting Polypeptide ◽  
Type Area ◽  
Sources Of Variation ◽  
Kidney Liver

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 [14C]hydroxyurea distribution in plasma, kidney, liver, urine, or the exhaled14CO2metabolite. 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 exhaled14CO2. 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.

scholarly journals A human photoacoustic imaging reporter gene using the clinical dye indocyanine green

2019 ◽  
Author(s):  
Nivin N. Nyström ◽  
Lawrence C.M. Yip ◽  
Jeffrey J.L. Carson ◽  
Timothy J. Scholl ◽  
John A. Ronald
Keyword(s):  
Indocyanine Green ◽  
Cell Tracking ◽  
Photoacoustic Imaging ◽  
Organic Anion ◽  
Reporter System ◽  
Optical Contrast ◽  
Organic Anion Transporting Polypeptide ◽  
Gene Therapies

ABSTRACTPhotoacoustic imaging (PAI) combines optical contrast with the resolution and depth-detection of ultrasound and is increasingly being utilized for medical imaging in patients. PAI reporter genes would allow for monitoring of cell and gene therapies, but current reporters have immunogenicity and/or toxicity concerns that may limit clinical translation. Here we report a PAI reporter system employing the ability of human organic anion transporting polypeptide 1b3 (Oatp1b3) to take up the clinical dye indocyanine green (ICG) into cells. Following ICG administration, cells synthetically expressing Oatp1b3 exhibited significantly increased PAI signals compared to control cells both in vitro and in mice. Several benefits of this technology are the human derivation of Oatp1b3, and the high extinction coefficient, low quantum yield and pre-existing clinical approval of ICG. We posit that the Oatp1b3-ICG reporter system could be useful for in vivo gene and cell tracking in preclinical and clinical applications.

Organic Anion Transporting Polypeptide 1B (OATP1B) Transporters Modulate Hydroxyurea Pharmacokinetics

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1008-1008
Author(s):  
Aisha L. Walker ◽  
Cynthia S Lancaster ◽  
Russell E. Ware ◽  
Alex Sparreboom
Keyword(s):  
Mouse Model ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Organic Anion ◽  
In Vitro Studies ◽  
Xenopus Laevis Oocytes ◽  
Organic Anion Transporting Polypeptide ◽  
Blood Disorder

Abstract Abstract 1008 Background: Sickle cell is the most common inherited blood disorder affecting millions worldwide. Hydroxyurea is currently the only FDA approved drug for the treatment of sickle cell anemia (SCA) that alters disease pathophysiology. Known for inducing fetal hemoglobin production, hydroxyurea can decrease hospitalizations, vaso-occlusive pain episodes, and mortality associated with SCA. Although efficacious for many patients, a large degree of inter-patient variability in pharmacokinetic (PK) and pharmacodynamic (PD) properties of hydroxyurea has been noted, but sources of this variation remain largely undefined. Plasma transmembrane transporters have been shown to play an important role in the determination drug PK and PD of various xenobiotics. Our recent in vitro studies have demonstrated that hydroxyurea is a substrate for specific solute carrier (SLC) transporters including members of the organic anion transporting polypeptide 1B (OATP1B) subfamily which consists of OATP1B1, and OATP1B3 in humans, and one mouse orthologue Oatp1b2. These transporters are highly expressed on the sinusoidal membrane of hepatocytes, and function as uptake transporters bringing substrates from the blood into the liver. Limited reports have suggested that Oatp1b2 transcript is also found in kidney and intestine as well. In the present study we evaluated the uptake of the hydroxyurea by different haplotypes of hOATP1B3 transporter in vitro, as well as the influence of the Oatp1b2 transporter on hydroxyurea PK in vivo using a transporter knock-out mouse model. Methods: Transporter-mediated cellular uptake of hydroxyurea was determined in vitro by measuring [14C]-hydroxyurea accumulation in Xenopus laevis oocytes that over express two common haplotypes of OATP1B3. hOATP1B3*1 and the functional variant hOATP1B3*2 that contains the 334T>G and 699G>A SNPs were assessed. In vivo PK Studies were performed using a knockout model mouse model in which mOATP1b2 was eliminated from the DBA/LcaJ1 background. Mice were dose with 50mg/kg of [14C]-hydroxyurea via oral gavage or intravenous (i.v.) injection. Serial blood samples were collected at defined timepoints and concluded with terminal blood and tissue collections at 2 hours post injection. Hydroxyurea levels were determined based on radioactivity in plasma and liver, and kidney homogenate. Accumulation in the urine was also measured over a 3 day period. Results: In vitro kinetic studies did not show any differences between OATP1B3*1 and OATP1B3*2 haplotypes in time-, or concentration-dependent accumulation of hydroxyurea. The inhibitor substrates naringen and rifampin decreased hydroxyurea accumulation by at least 50% in OATP1B3*1 but did not decrease accumulation in OATP1B3*2. These in vitro studies suggest that the genetic mutations associated with these two haplotypes do not have a functional impact on the transport of hydroxyurea, but may have significant implications for potential drug-drug interaction. In vivo, Hydroxyurea PK was altered in the absence of the Oatp1b2 transporter. Plasma levels of hydroxyurea were similar after i.v. injections, but total exposure (AUC) in Oatp1b2-KO mice was decreased by 20% with an AUC of 2257 mg-min/ml compared to 2872 mg-min/ml observed in the wildtype mice (p=0.04). Hydroxyurea levels in the kidneys of Oatp1b2-KO mice were approximately 50% of wildtype with a mean accumulation of 360 pmol/g tissue (p= 0.0025). In addition, 30% less hydroxyurea was excreted in urine of Oatp1b2-KO mice by 72 hours (p=0.023). Accumulation of hydroxyurea in liver of Oatp1b2-KO mice and wildtype mice were 107 and 132 pmol/g tissue respectively, but this difference was not statistically significant. These results suggest that hydroxyurea PK is altered in the absence of Oatp1b2 transporter after oral administration. Conclusions: These studies provide the first in vivo evidence that specific transporters may be key determinants of hydroxyurea PK. Future studies are warranted to investigate the influence of human OATP1B and other transporters that modulate hydroxyurea PK. Identification of such transporters may help to elucidate factors such as genetic variations in the transporters and/or drug-drug interactions that may contribute to PK and PD variability observed in sickle cell patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Inhibition of the organic anion-transporting polypeptide 1B1 by quercetin: an in vitro and in vivo assessment

2012 ◽  
Vol 73 (5) ◽  
pp. 750-757 ◽  
Author(s):  
Lan-Xiang Wu ◽  
Cheng-Xian Guo ◽  
Wang-Qing Chen ◽  
Jing Yu ◽  
Qiang Qu ◽  
...  
Keyword(s):  
Organic Anion ◽  
Organic Anion Transporting Polypeptide ◽  
In Vivo Assessment
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