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

We show here a 10-fold increased oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833

J van Asperen

2011

Scholarcy highlights

  • Oral administration of paclitaxel would offer several advantages, namely medication would no longer require a visit to the out-patient clinic, it may allow the achievement of lasting therapeutic plasma levels and it could prevent the adverse effects caused by the vehicle substance Cremophor EL
  • The search for agents that may help to restore the drug sensitivity of multidrug resistance tumour cells has led to the identification and clinical testing of potent P-glycoprotein blockers, such as the non-immunosuppressive cyclosporin analogue SDZ PSC 833
  • From 20% to 210%, suggesting that, apart from the effect of SDZ PSC 833 on intestinal paclitaxel uptake by P-glycoprotein inhibition, the increased systemic exposure results from the interaction of this agent with drug elimination pathways. This is supported by the fact that only a fivefold higher maximum plasma concentration of paclitaxel was observed in mice treated with SDZ PSC 833 compared with the 'control' group, whereas the corresponding area under the plasma concentration-time curve of paclitaxel was increased by a factor of ten
  • Combined treatment with SDZ PSC 833 resulted in a marked increase in the AUCorai of paclitaxel from 735 ± 134 ng h ml-' in the 'control group' to 8066 ± 819 ng h ml-l in the group treated in combination with SDZ PSC 833
  • Our results show a strikingly increased AUCorai of paclitaxel in the group treated in combination with SDZ PSC 833 compared with the 'control' group
  • area under the plasma concentration-time curve obtained after intravenous administration of paclitaxel in Cremophor EL-free formulations were used as Cremophor EL causes non-linear pharmacokinetic behaviour of paclitaxel

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