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 13 publications

(2 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The observed trend indicating more Pgp activity in rodents compared to human studies would in this case be even more pronounced. Uptake transporter activity potentially differs between species and could become important when compounds would be substrates such as paclitaxel which is described to be a substrate for hepatic OATP2B1 (Tanino et al 2009). However, species differences in uptake transporter activity are unknown and for most Pgp substrates reported here, no BBB uptake transporter activity has been described.…”

Section: Discussionmentioning

confidence: 99%

Differences in P-glycoprotein activity in human and rodent blood–brain barrier assessed by mechanistic modelling

et al. 2021

View full text Add to dashboard Cite

Variation in the efficacy and safety of central nervous system drugs between humans and rodents can be explained by physiological differences between species. An important factor could be P-glycoprotein (Pgp) activity in the blood–brain barrier (BBB), as BBB expression of this drug efflux transporter is reportedly lower in humans compared to mouse and rat and subject to an age-dependent increase. This might complicate animal to human extrapolation of brain drug disposition and toxicity, especially in children. In this study, the potential species-specific effect of BBB Pgp activity on brain drug exposure was investigated. An age-dependent brain PBPK model was used to predict cerebrospinal fluid and brain mass concentrations of Pgp substrate drugs. For digoxin, verapamil and quinidine, in vitro kinetic data on their transport by Pgp were derived from literature and used to scale to in vivo parameters. In addition, age-specific digoxin transport was simulated for children with a postnatal age between 25 and 81 days. BBB Pgp activity in the model was optimized using measured CSF data for the Pgp substrates ivermectin, indinavir, vincristine, docetaxel, paclitaxel, olanzapine and citalopram, as no useful in vitro data were available. Inclusion of Pgp activity in the model resulted in optimized predictions of their brain concentration. Total brain-to-plasma AUC values (Kp,brain) in the simulations without Pgp were divided by the Kp,brain values with Pgp. Kp ratios ranged from 1 to 45 for the substrates investigated. Comparison of human with rodent Kp,brain ratios indicated ≥ twofold lower values in human for digoxin, verapamil, indinavir, paclitaxel and citalopram and ≥ twofold higher values for vincristine. In conclusion, BBB Pgp activity appears species-specific. An age-dependent PBPK model-based approach could be useful to extrapolate animal data to human adult and paediatric predictions by taking into account species-specific and developmental BBB Pgp expression.

show abstract

Section: Discussionmentioning

confidence: 99%

Differences in P-glycoprotein activity in human and rodent blood–brain barrier assessed by mechanistic modelling

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Mrp3 mRNA in wild-type mouse liver, but not in PXR-null mice. [32] Other studies also showed that PCN increased oatp2 protein level in hepatocytes, [33,34] regulated the expression of organic cation transporters in rats [35] and UDP-glucuronosyltransferases mRNA expression in the liver. [36] We have noted that the UA was the substrate of OATPs/Oatps in one of our previous study.…”

Section: Metabolism Kinetics Of Uamentioning

confidence: 95%

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

Wen

Zhou

2020

Archiv der Pharmazie

View full text Add to dashboard Cite

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.

show abstract

Therapeutic potential of taxanes in the treatment of metastatic pancreatic cancer

Lemstrova

Melichar

Mohelníková-Duchoňová

2016

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

Most patients with pancreatic ductal adenocarcinoma (PDAC) present with unresectable or metastatic disease with very poor prognosis. Chemotherapy is the primary treatment modality for patients with locally advanced and metastatic PDAC, but the efficacy of currently available regimens is limited. Taxanes are widely used in many primary cancers including breast, ovarian and lung cancers. The activity of combined regimen of taxanes plus nucleoside analogue or platinum derivate in terms of response rate ranges between 20 and 57 % in PDAC and may prolong overall survival. Since 2013 nab-paclitaxel (paclitaxel-albumin-bound particles) became a new treatment option for patients with metastatic pancreatic cancer based on the results of MPACT trial. Moreover, encouraging activity in PDAC of the combination regimen of paclitaxel and carboplatin that is being widely used in other solid tumors has been reported recently. Biomarkers, including biomarkers predictive of taxane resistance, could allow individualized tailored therapy. BRCA mutation status could serve as predictor of better chemotherapy treatment outcome in PDAC. The present review summarizes the principal clinical trials evaluating the efficacy of taxanes both as monotherapy and in combination in view of the potential use in the treatment of PDAC.

show abstract

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 13 publications

References 0 publications

Differences in P-glycoprotein activity in human and rodent blood–brain barrier assessed by mechanistic modelling

Differences in P-glycoprotein activity in human and rodent blood–brain barrier assessed by mechanistic modelling

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

Therapeutic potential of taxanes in the treatment of metastatic pancreatic cancer

Contact Info

Product

Resources

About