Quantitative analysis of the P-glycoprotein inhibitor Elacridar (GF120918) in human and dog plasma using liquid chromatography with tandem mass spectrometric detection.
A liquid chromatographic/tandem mass spectrometric (LC/MS/MS) method for the determination of the P-glycoprotein and breast cancer resistance protein inhibitor Elacridar in human and dog plasma is described. The internal standard was stable isotopically labelled Elacridar. Sample pretreatment involved liquid-liquid extraction with tert-butyl methyl ether. Analysis of Elacridar and internal standard was performed by reversed-phase LC on a basic stable minibore analytical column with an eluent consisting of acetonitrile and aqueous ammonia. An API-2000 triple-quadrupole mass spectrometer with an electrospray ion source was used in the positive-ion multiple reaction monitoring mode. The run time per sample was only 6 min. The method is sensitive and specific, with a dynamic range from 1 to 500 ng ml(-1) from 100 microl of human or dog plasma. The accuracy of the method was within 15% bias and the precision was lower than 15% for all tested concentration levels and in both matrices. The method is simple and the liquid-liquid extraction produces clean samples. This method was successfully applied to support the pharmacokinetics of a clinical trial in which orally applied Elacridar was used as a bioavailability enhancer.
Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. apress@slz.nl
Ellen
E
Stokvis
Hilde
H
Rosing
Roger C
RC
Causon
Jan H M
JH
Schellens
Jos H
JH
Beijnen
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000166:Acridines / Q000008:administration & dosage / Q000032:analysis*; D000818:Animals; D002138:Calibration; D002853:Chromatography, Liquid / Q000379:methods* / Q000592:standards; D002986:Clinical Trials as Topic; D004285:Dogs; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods* / Q000592:standards; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000032:analysis* / Q000097:blood*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D044005:Tetrahydroisoquinolines; C083501:Elacridar