Liposomal lurtotecan (NX211): determination of total drug levels in human plasma and urine by reversed-phase high-performance liquid chromatography.
Lurtotecan (GI147211; LRT) is a semisynthetic and water-soluble analogue of the topoisomerase I inhibitor camptothecin. To determine whether the therapeutic efficacy of LRT in patients could be improved, the drug was encapsulated in liposomes (NX211; Gilead Sciences). In order to allow accurate description of the pharmacokinetic behavior of NX211 in cancer patients, we have developed sensitive RP-HPLC assays with fluorescence detection (lambdaex=378 nm; lambdaem=420 nm) for the determination of total LRT levels in human plasma and urine. Sample pretreatment involved deproteinization with 10% (w/v) aqueous perchloric acid-acetonitrile (2:1, v/v), and chromatographic separations were achieved on an Inertsil-ODS 80A analytical column. The lower limit of quantitation (LLQ) was established at 1.00 ng/ml in plasma (200-microl sample) and at 100 ng/ml in urine (200 microl of 40-fold diluted sample). The within-run and between-run precisions were <7.5%. LRT concentrations in urine of <100 ng/ml were determined by a modified procedure comprising a single solvent extraction with n-butanol-diethyl ether (3:4, v/v). In this assay, the fluorescence signal of LRT was increased 14-fold prior to detection by post-column exposure to UV light (254 nm) in a photochemical reaction unit. The LLQ of this assay was 0.500 ng/ml (150-microl sample) and the within-run and between-run precisions were <10%.
Loos
W J
WJ
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), The Netherlands. loos@pcnh.azr.nl
Kehrer
D
D
Brouwer
E
E
Verweij
J
J
de Bruijn
P
P
Hamilton
M
M
Gill
S
S
Nooter
K
K
Stoter
G
G
Sparreboom
A
A
D000097:Acetonitriles; D000970:Antineoplastic Agents / Q000097:blood* / Q000652:urine*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000652:urine; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D006801:Humans; D010472:Perchlorates; D012680:Sensitivity and Specificity
D000097:Acetonitriles; D000970:Antineoplastic Agents; D010472:Perchlorates; C091719:lurtotecan; D002166:Camptothecin; C032159:acetonitrile