Organic anion transporting polypeptide 2-mediated uptake of paclitaxel and 2′-ethylcarbonate-linked paclitaxel in freshly isolated rat hepatocytes

Tanino, Tadatoshi; Nawa, Akihiro; Nakao, Mao; Noda, Minoru; Fujiwara, S.; Iwaki, Masaya

doi:10.1211/jpp.61.08.0006

Cited by 8 publications

(10 citation statements)

References 38 publications

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“…Interestingly, however, the results of the present study show that the saturable (transporter-mediated) component accounts for 78.4% of the whole docetaxel sinusoidal uptake process into isolated rat hepatocytes, which is a key determinant of the overall hepatic elimination of docetaxel in rats. This is consistent with a previous study reporting a profound impact of Oatp1a/1b on the disposition of paclitaxel, a structurally-similar compound to docetaxel (van de Steeg et al, 2011). In the study, paclitaxel systemic exposure (at 10 mg/kg) was increased by greater than two-fold in Oatp1a/1b knockout mice compared with wild-type, whereas paclitaxel liver uptake was reduced by about two-fold.…”

Section: Discussionsupporting

confidence: 92%

“…Consistent with these studies, rifampicin exhibited an inhibitory effect on in vitro metabolism of docetaxel, showing the inhibition only at the highest concentration tested (100 μM) ( Figure 4B). The hepatic sinusoidal uptake of docetaxel was investigated using isolated rat hepatocytes, which are widely accepted as a 'gold standard' for providing a reliable evaluation of drug uptake across sinusoidal membrane (Hirano et al, 2004;Lam et al, 2006;Tanino et al, 2009). Unlike in transfected systems, there is no published information regarding docetaxel uptake in isolated rat hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Docetaxel is a hydrophobic compound without an anionic moiety at physiological pH, which has been considered to readily pass the sinusoidal membrane by passive diffusion (Tanino et al, 2009). Thus, one concern that transporter (Oatps)-mediated docetaxel uptake may not play a significant role in docetaxel pharmacokinetics can be raised.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a significant association of single nucleotide polymorphism in SLCO1B3 with the toxicity of docetaxel (leucopenia) has been reported (Kiyotani et al, 2008). More recent study has also demonstrated that Oatp1a and 1b have a profound impact on the pharmacokinetics of paclitaxel in mice (van de Steeg et al, 2011). However, the kinetics of sinusoidal uptake of docetaxel and its impact on the overall hepatic elimination of docetaxel remain poorly understood in animals and human.…”

Section: Research Articlementioning

confidence: 99%

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Saturable sinusoidal uptake is rate-determining process in hepatic elimination of docetaxel in rats

et al. 2012

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Research Articlementioning

confidence: 99%

See 2 more Smart Citations

Saturable sinusoidal uptake is rate-determining process in hepatic elimination of docetaxel in rats

et al. 2012

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“…Also, other uptake transporters are present at the basolateral membrane of the liver: for instance, organic anion transporter 2 (OAT2; SLC22A7). Human OAT2, but not its murine ortholog Oat2, was also shown to be a transporter of PTX in vitro, with a K m value of about 0.15 mmol/L (30,31). Therefore, OATP1B3 might act together with OAT2 in the hepatic uptake of PTX in humans.…”

Section: A B Cmentioning

confidence: 96%

High Impact of Oatp1a/1b Transporters on In Vivo Disposition of the Hydrophobic Anticancer Drug Paclitaxel

Steeg

Esch

Wagenaar

et al. 2011

Clinical Cancer Research

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Purpose: Organic anion-transporting polypeptides (OATP) mediate the cellular uptake of a broad range of drugs. The hydrophobic anticancer drug, paclitaxel (PTX), was recently identified as a substrate for OATP1B3 in vitro. We investigated the role of Oatp1a/1b transporters in the pharmacokinetics of PTX in vivo, as well as their impact at different dose levels of PTX and methotrexate (MTX).Experimental Design: Recently generated Slco1a/1b À/À (lacking all Oatp1a/1b transporters) and wildtype mice were intravenously dosed with 2, 10, or 50 mg/kg of PTX, or with 10, 50, or 500 mg/kg of MTX, and plasma and tissue drug concentrations were measured.Results: In spite of its hydrophobicity, PTX systemic exposure (at 10 mg/kg) was increased by greater than 2-fold in Slco1a/1b À/À mice compared with wild-type, whereas PTX liver uptake was reduced by about 2-fold. Oatp1a/1b transporters displayed a high impact on PTX and MTX pharmacokinetics over a broad dose range. For MTX, even at 500 mg/kg, saturation of Oatp1a/1b was not observed, with a 3.4-fold increase in plasma and 30-fold decrease in liver levels in Slco1a/1b À/À mice compared with wild-type.Although beginning saturation of Oatp1a/1b was observed at the highest dose of PTX, plasma levels in Slco1a/1b À/À mice were still 1.7-fold increased and liver levels 1.5-fold decreased compared with wild-type.Conclusion: Oatp1a/1b transporters play a pronounced role in determining plasma levels and tissue distribution of MTX and PTX, thus affecting even highly hydrophobic drugs. Variation in OATP1A/1B transporter activity, due to genetic variation, inhibition, and/or tumor expression might affect toxicity and therapeutic efficacy of these anticancer drugs.

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PXR–ABC drug transporters/CYP‐mediated ursolic acid transport and metabolism in vitro and vivo

Wen

Zhou

2020

Archiv der Pharmazie

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The transporting kinetics and metabolic kinetics of ursolic acid were studied in transgenic cell models. Then, the pharmacokinetics features of ursolic acid and the expression of ATP‐binding cassette transporters (ABC transporter) and cytochrome P450 (CYP) enzymes in tissues after pregnane X receptor (PXR) activation by 5‐pregnen‐3β‐ol‐20‐one‐16α‐carbonitrile (PCN) were investigated in rats. After silencing of PXR in Caco2–siRNA–PXR cells, there was a decrease in the protein abundance of P‐glycoprotein, breast cancer‐resistant protein, multidrug resistance‐associated protein 2 (MRP2), and CYP2C9. The apparent permeability (PDR) values of 10, 20, and 50 µM ursolic acid in Caco2 cells were 2.19 ± 0.44, 1.40 ± 0.17, and 1.25 ± 0.07, respectively, whereas in Caco2–siRNA–PXR cells, they were 1.85 ± 0.36, 1.24 ± 0.11, and 1.19 ± 0.04, respectively. PXR–RXRα would significantly activate ABC transporter expression in Caco2 cells. Compared with Caco2 cells, when the concentrations of ursolic acid were 10, 20, and 50 µM, the PDR values increased in Caco2–PXR–RXRα cells after PXR activation: 1.60 ± 0.31 versus 1.97 ± 0.21, 1.46 ± 0.08 versus 2.01 ± 0.19, and 1.32 ± 0.26 versus 2.09 ± 0.22, respectively. Simultaneously, PXR–RXRα would activate the expression of CYP2C9; metabolic kinetics of ursolic acid in CYP metabolizing enzyme lysate of Caco2 cells and Caco2–PXR–RXR cells was studied and it was found that the Km values were 81.99 ± 44.32 and 60.05 ± 29.62 µg/ml, and Vmax values were 3.77 ± 0.86 and 3.41 ± 0.96 µg · ml−1 · min−1, respectively. However, in human CYP metabolizing recombinase, we found that both CYP2C9 and CYP34A were involved in the metabolism of ursolic acid. Vm and Km values for CYP3A4 and CYP2C9 were 3.57 ± 1.12 µg · ml−1 · min−1 and 81.71 ± 18.38 µg/ml, 3.85 ± 1.46 µg · ml−1 · min−1 and 62.18 ± 14.56 µg/ml, respectively. As a strong agonist for mouse pxr, PCN could significantly affect pharmacokinetics of ursolic acid in rats, and it showed discrepant effects on messenger RNA expression of cyp and transporters in tissues.

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Organic anion transporting polypeptide 2-mediated uptake of paclitaxel and 2′-ethylcarbonate-linked paclitaxel in freshly isolated rat hepatocytes

Abstract: The findings have provided an important step towards identifying a key transporter in hepatic detoxification of paclitaxel and TAX-2'-Et in small animals.

Cited by 8 publications

References 38 publications

Saturable sinusoidal uptake is rate-determining process in hepatic elimination of docetaxel in rats

Saturable sinusoidal uptake is rate-determining process in hepatic elimination of docetaxel in rats

High Impact of Oatp1a/1b Transporters on In Vivo Disposition of the Hydrophobic Anticancer Drug Paclitaxel

PXR–ABC drug transporters/CYP‐mediated ursolic acid transport and metabolism in vitro and vivo

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