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Valspodar: current status and perspectives.
1Université de Strasbourg 1, Fédération de Recherches Biotechnologie et Médicament, Laboratoire d'Immunologie, BP 24, F-67401 Illkirch, France. loor@aspirine.u-strasbg.fr
Expert Opinion on Investigational Drugs
|July 5, 2005
Summary
Valspodar effectively chemosensitizes multidrug-resistant (MDR) tumor cells by inhibiting P-glycoprotein (Pgp) function. This drug shows promise in clinical trials for enhancing chemotherapy efficacy and potentially aiding drug delivery to the brain.
Area of Science:
- Pharmacology
- Oncology
- Drug Metabolism
Background:
- Valspodar, a cyclosporin derivative, lacks immunosuppressive properties but enhances chemosensitization of multidrug-resistant (MDR) tumor cells.
- MDR is often associated with P-glycoprotein (Pgp) overexpression, a key factor in chemotherapy failure.
Purpose of the Study:
- To review the mechanism of valspodar-mediated chemosensitization of MDR tumor cells.
- To discuss valspodar's potential inhibition of anticancer drug (ACD) metabolism by CYP3A enzymes.
- To evaluate valspodar's pharmacokinetic interactions and clinical efficacy.
Main Methods:
- Review of preclinical and clinical data on valspodar's mechanism of action.
- Analysis of valspodar's inhibition of Pgp flippase function.
- Discussion of valspodar's interactions with CYP3A enzymes and Pgp substrates.
Main Results:
- Valspodar potently inhibits Pgp and may inhibit CYP3A-mediated drug metabolism.
- Valspodar causes significant pharmacokinetic interactions with drugs that are substrates of Pgp and/or CYP enzymes.
- Clinical data suggest optimism for ongoing Phase III trials regarding valspodar's efficacy and safety.
Conclusions:
- Valspodar effectively chemosensitizes MDR tumor cells via Pgp inhibition.
- Valspodar's pharmacokinetic interactions require careful management of chemotherapeutic dosages.
- Potential applications include enhancing the brain exposure of certain chemotherapeutics.