Highly Sensitive Quantitative Analysis of 1-[3-(Furo[3,2- c ]quinolin-4-ylamino)phenyl]ethanone Oxime, a New Antitumor Agent, in Rat Plasma by LC with Electrochemical Detection

1-[3-(Furo[3,2- c ]quinolin-4-ylamino)phenyl]ethanone oxime (CCK2) is an antitumor agent which was especially active against the growth of the renal cancer cell UO-31 (GI 50 = 0.03 μ m ) and the two melanoma cancer cells UACC-257 (GI 50 < 0.01 μ m ) and UACC-62 (GI 50 < 0.01 μ m ) in cytotoxicity evaluation of NCI’s full panel of 60 human cancer cell lines. From structure–activity relationships for amsacrine and CCK2, CCK2 is, moreover, expected to have a longer half-life than amsacrine in plasma. A sensitive high-performance liquid chromatographic method with electrochemical detection has therefore been developed and validated for determination of the pharmacokinetics of CCK2 in rats. Plasma samples were spiked with 2-naphthol as internal standard and extracted with dichloromethane. The analytes were separated on a C 18 reversed-phase column (55 × 4 mm) with 20% acetonitrile, 5% tetrahydrofuran, and 75% pH 3.0 McIlvaine buffer as mobile phase at a flow rate of 1.0 mL min −1 . Electrochemical detection of CCK2 was performed at 1.0 V and 20 nA. Intra-day and inter-day precision and accuracy were acceptable down to the limit of quantification of 10 ng mL −1 . The lower limit of detection was 5 ng mL −1 . In an in vivo study pharmacokinetic data were determined for CCK2 in rat after intravenous administration of 6, 12, and 24 μmol kg −1 . The apparent volume of distribution, elimination half-life, and clearance were not significantly different among the three doses. The area under the plasma concentration–time curve increased in proportion to increasing dose. The elimination half-life of CCK2 was 3.4 times that of amsacrine. CCK2 might, therefore, have the potential to be tested clinically. The results also showed that this selective, sensitive, and reproducible LC method could be successfully applied to investigation of the pharmacokinetics of CCK2.