Validation study of a method for assaying DE-310, a macromolecular carrier conjugate containing an anti-tumor camptothecin derivative, and the free drug in tumor tissue by high performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry.
DE-310 is a macromolecular carrier conjugate containing an anti-tumor camptothecin derivative, DX-8951, which is conjugated to a water-soluble polymer via a peptide spacer. Assay methods have been developed for the determination of a polymer-bonded DX-8951 conjugate, DX-8951, and Glycyl-DX-8951 concentrations in murine Meth A tumor tissue. Free DX-8951 and Glycyl-DX-8951 were extracted from tumor tissue homogenates by protein precipitation and analyzed by LC/MS/MS (method I). Conjugated DX-8951 was isolated by solid-phase extraction after digestion with a thermolysin. The productive phenylalanyl-glycyl-DX-8951 was analyzed by LC/MS/MS (method II). The lower limits of quantitation of DX-8951, Glycyl-DX-8951, and conjugated DX-8951 were 1.36, 1.34 and 73.7 ng/g (as DX-8951 equivalent). These two methods showed satisfactory sensitivity, precision and accuracy. To study the pharmacokinetics of DE-310, it would be of great help to assay the polymer-bonded DX-8951 and its released drugs in tumor tissue.
Drug Metabolism and Physicochemical Property Research Laboratory, Daiichi Pharmaceutical Co. Ltd, Tokyo 134-8630, Japan. ogumab0g@daiichipharm.co.jp
Toshihiro
T
Oguma
Hiroshi
H
Morikawa
Daisuke
D
Iwasaki
Ryo
R
Atsumi
D000818:Animals; D001274:Atmospheric Pressure; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000032:analysis / Q000302:isolation & purification* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004337:Drug Carriers / Q000032:analysis; D004355:Drug Stability; D005354:Fibrosarcoma / Q000737:chemistry; D005615:Freezing; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
C452060:DE-310 cpd; D004337:Drug Carriers; C501379:glycyl-DX-8951; C095887:exatecan; D002166:Camptothecin