TY - JOUR
T1 - Development and validation of LC-MS/MS assays for the quantification of E7080 and metabolites in various human biological matrices
AU - Dubbelman, A.C.
AU - Rosing, H.
AU - Thijssen, B
AU - Gebretensae, A.
AU - Lucas, L.
AU - Chen, H.
AU - Shumaker, R.
AU - Schellens, J.H.M.
AU - Beijnen, J.H.
PY - 2012
Y1 - 2012
N2 - To support clinical pharmacokinetic studies with the anticancer agent E7080 (lenvatinib), liquid chromatography tandem mass spectrometry (LC-MS/MS) methods were developed for the quantification of E7080 and four of its metabolites in human plasma, urine and faeces and of E7080 in whole blood. Cross-analyte interferences between metabolites and parent compound were expected and therefore accounted for early in the method development. Plasma, urine and faeces samples were extracted with acetonitrile. Chromatographic separation was achieved on a 50 mm x 2.1 mm I.D. XTerra MS C18 column, with a 0.2 mL/min flow and gradient elution starting with 100% formic acid in water, followed by an increasing percentage of acetonitrile. Whole blood samples were extracted with diethyl ether and extracts were injected on a 150 mm x 2.1mm I.D. Symmetry Shield RP8 column. Detection was performed using an API3000 triple quadrupole mass spectrometer, with a turbo ion spray interface, operating in positive ion mode. Using 250 muL of plasma, E7080 and its metabolites could be quantified between 0.25 and 50.0ng/mL. The quantifiable ranges of E7080 in whole blood, urine and faeces were 0.25-500 ng/mL, 1.00-500 ng/mL and 0.1-25mug/g, using sample volumes of 250 muL, 200 muL and 250 mg, respectively. Calibration curves in all matrices were linear with a correlation coefficient (r(2)) of 0.994 or better. At the lower limit of quantification, accuracies were within +/-20% of the nominal concentration with CV values less than 20%. At the other concentrations the accuracies were within +/-15% of the nominal concentration with CV values below 15%. The developed methods have successfully been applied in a mass balance study of E7080.
AB - To support clinical pharmacokinetic studies with the anticancer agent E7080 (lenvatinib), liquid chromatography tandem mass spectrometry (LC-MS/MS) methods were developed for the quantification of E7080 and four of its metabolites in human plasma, urine and faeces and of E7080 in whole blood. Cross-analyte interferences between metabolites and parent compound were expected and therefore accounted for early in the method development. Plasma, urine and faeces samples were extracted with acetonitrile. Chromatographic separation was achieved on a 50 mm x 2.1 mm I.D. XTerra MS C18 column, with a 0.2 mL/min flow and gradient elution starting with 100% formic acid in water, followed by an increasing percentage of acetonitrile. Whole blood samples were extracted with diethyl ether and extracts were injected on a 150 mm x 2.1mm I.D. Symmetry Shield RP8 column. Detection was performed using an API3000 triple quadrupole mass spectrometer, with a turbo ion spray interface, operating in positive ion mode. Using 250 muL of plasma, E7080 and its metabolites could be quantified between 0.25 and 50.0ng/mL. The quantifiable ranges of E7080 in whole blood, urine and faeces were 0.25-500 ng/mL, 1.00-500 ng/mL and 0.1-25mug/g, using sample volumes of 250 muL, 200 muL and 250 mg, respectively. Calibration curves in all matrices were linear with a correlation coefficient (r(2)) of 0.994 or better. At the lower limit of quantification, accuracies were within +/-20% of the nominal concentration with CV values less than 20%. At the other concentrations the accuracies were within +/-15% of the nominal concentration with CV values below 15%. The developed methods have successfully been applied in a mass balance study of E7080.
M3 - Article
SN - 1570-0232
VL - 887-888
SP - 25
EP - 34
JO - Journal of chromatography. B
JF - Journal of chromatography. B
ER -