Pharmacokinetics of PSC 833 (valspodar) in its Cremophor EL formulation in rat

Abstract

1. Valspodar is a P-glycoprotein inhibitor widely used in preclinical and clinical studies for overcoming multidrug resistance. Despite this, the pharmacokinetics of valspodar in rat, a commonly used animal model, have not been reported. Here, we report on the pharmacokinetics of valspodar in Sprague–Dawley rats following intravenous and oral administration of its Cremophor EL formulation, which has been used for humans in clinical trials.

2. After intravenous doses, valspodar displayed properties of slow clearance and a large volume of distribution. Its plasma unbound fraction was around 15% in the Cremophor EL formulation used in the study. After 10 mg kg⁻¹ orally it was rapidly absorbed with an average maximal plasma concentration of 1.48 mg l⁻¹ within approximately 2 h. The mean bioavailability of valspodar was 42.8%.

3. In rat, valspodar showed properties of low hepatic extraction and wide distribution, similar to that of its structural analogue cyclosporine A.

Keywords::

• Valspodar
• PSC 833
• pharmacokinetics
• metabolism
• protein binding

Acknowledgements

The authors acknowledge funding from Alberta Heritage for Medical Research (AHFMR). The authors would like to thank Novartis for providing the drug (valspodar) used in this study. Z. Binkhathlan was supported by a scholarship from King Saud University, Saudi Arabia. D. A. Hamdy was supported by a studentship from government of Egypt.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.