The influence of P-glycoprotein on morphine transport in Caco-2 cells. Comparison with paclitaxel

Crowe, Andrew

doi:10.1016/s0014-2999(02)01366-3

Cited by 48 publications

(42 citation statements)

References 29 publications

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“…The amount of internalized peptide may also be kept low by efflux transporters present on the apical surface of the Caco-2 cell. P-glycoprotein is expressed on the apical surface of Caco-2 cells and has been shown to play a role in the efflux of morphine and paclitaxel (Crowe, 2002). In our study, incubation with verapamil, a P-glycoprotein inhibitor, had no effect on the uptake of [Dmt 1 ]DALDA, suggesting that Pglycoprotein was not involved in the efflux of [Dmt 1 ]DALDA.…”

Section: Discussioncontrasting

confidence: 46%

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Transcellular Transport of a Highly Polar 3+ Net Charge Opioid Tetrapeptide

Zhao

Luo²,

Zhao³

et al. 2003

J Pharmacol Exp Ther

143

118

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Oligopeptides are generally thought to have poor permeability across biological membranes. Recent studies, however, suggest significant distribution of [Dmt 1 ]DALDA (Dmt-D-Arg-PheLys-NH 2 ; Dmt is 2Ј,6Ј-dimethyltyrosine), a 3ϩ net charge opioid peptide, to the brain and spinal cord after subcutaneous administration. Peptide transporters (PEPT1 and PEPT2) play a major role in the uptake of di-and tripeptides across cell membranes, but their ability to transport tetrapeptides is not clear.

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Section: Discussioncontrasting

confidence: 46%

“…In our study, incubation with verapamil, a P-glycoprotein inhibitor, had no effect on the uptake of [Dmt 1 ]DALDA, suggesting that Pglycoprotein was not involved in the efflux of [Dmt 1 ]DALDA. In contrast, verapamil increased the uptake of paclitaxel Ͼ100-fold in Caco-2 cells (Crowe, 2002).…”

Section: Discussionmentioning

confidence: 88%

Transcellular Transport of a Highly Polar 3+ Net Charge Opioid Tetrapeptide

Zhao

Luo²,

Zhao³

et al. 2003

J Pharmacol Exp Ther

143

118

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“…Sorafenib showed an efflux ratio of Ͼ2 in Caco-2 cells. Compared with other substrates for efflux pumps such as digoxin (Balimane et al, 2004), paclitaxel (Taxol) (Crowe, 2002), or vinblastine (Tang et al, 2002), all showing efflux ratios higher than 10, the observed efflux ratio in Caco-2 cells for sorafenib was low.…”

Section: Discussionmentioning

confidence: 92%

In Vitro to In Vivo Comparison of the Substrate Characteristics of Sorafenib Tosylate toward P-Glycoprotein

Gnoth¹,

Sandmann²,

Engel³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Sorafenib (Nexavar) is a novel oral Raf kinase and vascular endothelial growth factor receptor inhibitor. Most anticancer drugs are substrates for ATP-binding cassette efflux pumps especially for P-glycoprotein (P-gp). To evaluate the influence of P-gp on the pharmacokinetics of sorafenib substrate properties for this transporter were investigated. Therefore, permeability of sorafenib across Caco-2 and P-gp-overexpressing cells was determined. To determine the in vivo relevance of these in vitro findings, pharmacokinetics of sorafenib in mdr1a/1b(؊/؊) and wild-type (WT) mice was studied. Sorafenib is highly permeable and exhibits a slight efflux across Caco-2 cells. In P-gp-overexpressing cells, a small concentration-dependent efflux was observed, which was completely blocked by the addition of ivermectin. In mdr1a/1b(؊/؊) and WT mice, unchanged compound represented by far the majority of radioactivity in plasma. After intravenous and oral administration, brain/plasma concentration ratios in mdr1a/1b(؊/؊) mice were 1.3-to 1.5-fold higher than those in WT mice. However, after intravenous or oral administration, plasma concentrations were similar in both mouse strains. In conclusion, sorafenib is highly permeable and a weak P-gp substrate in vitro. These findings were confirmed by the small factor of 1.3 to 1.5 observed for the brain/plasma ratios in mdr1a/1b(؊/؊) versus WT mice in vivo. Based on these in vitro and in vivo results, it is unlikely that P-gp has a major effect on the plasma concentrations of sorafenib in humans. Because of the high permeability and low P-gp-mediated transport, sorafenib might be able to cross the blood-brain barrier and target tumors within the brain.

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“…31 For this reason, a series of bidirectional transport studies were conducted using Caco-2 cells, a cell line known to express both P-gp and MRP. 34,35 These studies were performed to determine whether the permeabilities of oxycodone were modulated in the presence of P-gp or MRP inhibitors. Our results showed that absorptive transport from (A-B) was not significantly altered in the presence of either P-gp or MRP inhibitors ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Oxycodone induces overexpression of P‐glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats

Hassan

Myers

Lee

et al. 2007

Journal of Pharmaceutical Sciences

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Previous studies suggest that P-glycoprotein (P-gp) modulates the PK/PD of many compounds including opioid agonists and chemotherapeutic agents. The objective of this study was to assess the P-gp affinity status of oxycodone, the P-gp expression, and the paclitaxel's tissue distribution in oxycodone-treated rats. P-gp ATPase assay, Caco-2 transepithelial permeability studies, and mdr1a/b (−/−) mice were used to assess the P-gp affinity status of oxycodone. P-gp expression was determined by Western blot analysis while [ 14 C] paclitaxel's distributions in the liver, kidney, brain, and plasma tissues were determined by liquid scintillation counter. Oxycodone stimulated the P-gp ATPase activity in a concentration-dependant manner. The Caco-2 secretory transport of oxycodone was reduced from 3.64 ×10 −5 to 1.96 × 10 −5 cm/s (p <0.05) upon preincubation with the P-gp inhibitor, verapamil. The brain levels of oxycodone in mdr1a/b (+/+) were not detectable (<15 ng/mL) while in mdr1a/b (−/−) the average levels were 115 ± 39 ng/mL. The P-gp protein levels were increased by 1.3-4.0 folds while paclitaxel's tissue distributions were decreased by 38-90% (p <0.05) in oxycodone-treated rats. These findings display that oxycodone is a P-gp substrate, induces overexpression of P-gp, and affects paclitaxel's tissue distribution in a manner that may influence its chemotherapeutic activity.

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The influence of P-glycoprotein on morphine transport in Caco-2 cells. Comparison with paclitaxel

Cited by 48 publications

References 29 publications

Transcellular Transport of a Highly Polar 3+ Net Charge Opioid Tetrapeptide

Transcellular Transport of a Highly Polar 3+ Net Charge Opioid Tetrapeptide

In Vitro to In Vivo Comparison of the Substrate Characteristics of Sorafenib Tosylate toward P-Glycoprotein

Oxycodone induces overexpression of P‐glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats

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