Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833

Asperen, Judith van; Tellingen, Olaf van; Sparreboom, Alex; Schinkel, Alfred H.; Borst, Piet; Nooijen, W. J.; Beijnen, Jos H.

doi:10.1038/bjc.1997.530

Cited by 177 publications

(79 citation statements)

References 15 publications

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“…Studies in mice revealed that coadministration of SDZ PSC833, a cyclosporin D analogue and potent P-gp inhibitor, with paclitaxel resulted in a 10-fold increase in systemic exposure [103]. A similar study was performed with CsA and paclitaxel that has shown comparable effects [104].…”

Section: Paclitaxelmentioning

confidence: 99%

Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview

2002

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The oral bioavailability of many cytotoxic drugs is low and/or highly variable. This can be caused by high affinity for drug transporters and activity of metabolic enzymes in the gastrointestinal tract and liver. In this review, we will describe the main involved drug transporters and metabolic enzymes and discuss novel methods to improve oral treatment of affected substrate drugs. Results of preclinical and clinical phase I and II studies will be discussed in which affected substrate drugs, such as paclitaxel, docetaxel, and topotecan, are given orally in combination with an inhibitor of drug transport or drug metabolism. Future randomized studies will, hopefully, confirm that this strategy for oral treatment is at least as equally effective and safe as standard intravenous administration of these drugs. The Oncologist 2002;7:516-530

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Section: Paclitaxelmentioning

confidence: 99%

Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview

2002

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“…In human, CYP3A4 is the principal enzyme involved in the hepatic and intestinal drug metabolism, and there is a striking overlap of substrate specificites among CYP3A4, P-gp and MRPs. The coordinated function of both CYP3A and P-gp, MRPs can dramatically lower oral bioavailability of compounds which are substrates for both (van Asperen et al, 1997;Wacher et al, 1998) and this may also be true for LVR. P-gp mediated efflux of LVR has been published (Vishnuvardhan et al, 2003;Woodahl et al, 2005) but interactions of LVR with other adenosine triphosphate-binding cassette (ABC) efflux transporters such as MRPs and BCRP have not yet been investigated.…”

Section: Introductionmentioning

confidence: 99%

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

Agarwal

Pal

Mitra

2007

International Journal of Pharmaceutics

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Polarized epithelial non-human (canine) cell lines stably transfected with human or murine complementary DNA (cDNA) encoding for various efflux transporters (P-gp/MDR1, MRP1, MRP2, and Bcrp1) were used to study transepithelial transport of Lopinavir (LVR) and compare results with the MDCKII-Wild type cells. These transmembrane proteins cause multidrug resistance by decreasing the total intracellular accumulation of drugs. Lopinavir efflux was directional and was completely inhibited by MK-571, a selective MRP family inhibitor in the MDCKII-MRP2 cell line. Similarly, LVR efflux was also inhibited by P-gp inhibitors P-gp 4008 and GF120918 in the MDCKII-MDR1 cell line. The efflux ratios (Efflux rate/ Influx rate) of LVR in the absence of any efflux inhibitors in the MDCK-Wild type, MDCKII-MDR1, MDCKII-MRP1 and MDCKII-MRP2 cell monolayers were 1.32, 4.91, 1.26 and 2.89 respectively. The MDCKII-MDR1 and MDCKII-MRP2 cells have significantly increased LVR efflux ratio relative to the parental cells due to the apically directed transport by MDR1 and MRP2 respectively. The efflux ratios in MRP2 and MDR1 transfected cell lines were close to unity in the presence of MK-571 and P-gp 4008 respectively; indicating that LVR efflux by MRP2 and P-gp was completely inhibited by their selective inhibitors. MDCKII-MRP1 cells did not exhibit a significant reduction in the LVR efflux relative to the parental cells, indicating that LVR is not a good substrate for MRP1. Transport studies across MDCKII-Bcrp1 cells indicated that LVR is not transported by Bcrp1 and is not a substrate for this efflux protein. In conclusion, this study presents direct evidence that LVR is effluxed by both P-gp and MRP2 which may contribute to its poor oral bioavailability and limited penetration into the CNS. KeywordsMDCKII-MDR1; MDCKII-MRP2; MDCKII-MRP1; MDCKII-Bcrp1; MDCKII-WT; Pglycoprotein (P-gp); multidrug resistance protein (MRP); breast cancer resistance protein (BCRP); Lopinavir (LVR); uptake; transport; permeability; efflux ratio (ER)

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“…These properties of paclitaxel create expectations that paclitaxel could be a good therapeutic agent in the treatment of brain tumors. But as paclitaxel is one of the P-gp substrates (21)(22)(23), it cannot reach tumor cells in the brain parenchyma (24), which makes it hard to absorb orally administered paclitaxel from the gut lumen (15). Therefore, inhibition of P-pg activity is essential.…”

Section: Introductionmentioning

confidence: 99%

Oral paclitaxel chemotherapy for brain tumors: Ideal combination treatment of paclitaxel and P-glycoprotein inhibitor

Joo

Park²,

Kong³

et al. 2008

Oncol Rep

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Abstract. Oral chemotherapy has many advantages over parenteral chemotherapeutics administration. To use the advantages of the oral chemotherapy and maximize anti-tumor effects of the chemotherapeutic agent, we designed HM30181A (a P-glycoprotein inhibitor) and a paclitaxel oral co-administration chemotherapeutic method. HM30181A is used to aid paclitaxel absorption from gut lumen into blood and to inhibit paclitaxel exclusion out of the brain tumor mass by endothelial cells, which inhibits paclitaxel access to tumor cells in the brain parenchyma. We applied HM30181A and paclitaxel oral co-administration methods to the treatment of tumors in the brain using the K1735 melanoma brain metastasis animal model and the U-87 MG glioblastoma animal model. Administrations were performed twice per week for 28 days and the therapeutic effect was examined using tumor volume change. We observed that 32 mg/kg HM30181A and 16 mg/kg of paclitaxel (dose ratio 2:1) oral co-administration showed significant therapeutic effects in both animal models, but when the doses or dose ratio was changed, the effects could not be observed. Therefore, adjustments of doses and dose ratio of the agents seems to be essential in realizing oral HM30181A and paclitaxel treatment in brain tumors. These results suggest that if the doses and dose ratio can be successfully adjusted, the oral coadministration of HM30181A and paclitaxel can be used to treat tumors in the brain.

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Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833

Cited by 177 publications

References 15 publications

Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview

Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

Oral paclitaxel chemotherapy for brain tumors: Ideal combination treatment of paclitaxel and P-glycoprotein inhibitor

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