title: HPLC method for monitoring SDZ PSC 833 in whole blood.
abstract: P-glycoprotein (Pgp) is a 170-kDa membrane transporter that mediates drug efflux and is an effector of multidrug resistance. SDZ PSC 833 (PSC), a nonimmunosuppressive cyclosporine that potently modulates Pgp, is currently under clinical evaluation in patients with cancer. We have developed a reversed-phase HPLC assay for determining PSC blood concentrations that utilizes a step gradient with linear segments to resolve PSC into two distinct peaks (likely to be keto and enol isomers). To clinically validate the assay, PSC concentrations were obtained by HPLC from nine patients receiving oral doses of 5 mg/kg every 6 h. Values ranged from 0.91 to 5.4 mg/L during the dosing period, comparable with concentrations of PSC that modulate Pgp in vitro. In addition, we investigated the immunoreactivity of the Abbott TDx cyclosporin A (CsA) monoclonal whole-blood assay for PSC. The TDx CsA assay cross-reacts approximately 17% with PSC as determined by adding known amounts of PSC to whole blood. When PSC concentrations obtained by the TDx CsA assay were divided by 0.17, we found agreement between the TDx CsA assay and the HPLC PSC assay for samples from nine patients.
authors.affiliation: Division of Laboratory Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. mscott@labmed.wustl.edu
authors.forename: M G
authors.initials: MG
authors.lastname: Scott
authors.forename: K G
authors.initials: KG
authors.lastname: Hock
authors.forename: D L
authors.initials: DL
authors.lastname: Crimmins
authors.forename: P M
authors.initials: PM
authors.lastname: Fracasso
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D003429:Cross Reactions; D016572:Cyclosporine / Q000097:blood; D003524:Cyclosporins / Q000097:blood* / Q000627:therapeutic use; D016903:Drug Monitoring / Q000379:methods*; D016231:Fluorescence Polarization Immunoassay; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000627:therapeutic use; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy; D017239:Paclitaxel / Q000008:administration & dosage; D015203:Reproducibility of Results
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D017239:Paclitaxel; C070272:valspodar