title: Pharmacokinetics of PSC 833 (valspodar) in its Cremophor EL formulation in rat.
abstract: 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. 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%. In rat, valspodar showed properties of low hepatic extraction and wide distribution, similar to that of its structural analogue cyclosporine A.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2N8, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Binkhathlan
authors.forename: D A
authors.initials: DA
authors.lastname: Hamdy
authors.forename: D R
authors.initials: DR
authors.lastname: Brocks
authors.forename: A
authors.initials: A
authors.lastname: Lavasanifar
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000818:Animals; D003524:Cyclosporins / Q000493:pharmacokinetics*; D005990:Glycerol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; C000515:cremophor EL; D005990:Glycerol; C070272:valspodar