Analysis of aplidine (dehydrodidemnin B), a new marine-derived depsipeptide, in rat biological fluids by liquid chromatography-tandem mass spectrometry.
Aplidine (dehydrodidemnin B) is a new marine-derived depsipeptide with a powerful cytotoxic activity, which is under early clinical investigation in Europe and in the US. In order to investigate the pharmacokinetic properties of this novel drug, an HPLC-tandem mass spectrometry method was developed for the determination of aplidine in biological samples. Didemnin B, a hydroxy analogue, was used as internal standard. After protein precipitation with acetonitrile and extraction with chloroform, aplidine was chromatographed with a RP octadecylsilica column using a water-acetonitrile linear gradient in the presence of formic acid at the flow-rate of 500 microliters/min. The method was linear over a 5-100 ng/ml range (LOD = 0.5 ng/ml) in plasma and over a 1.25-125 ng/ml range (LOD = 0.2 ng/ml) in urine with precision and accuracy below 14.0%. The intra- and inter-day precision and accuracy were below 12.5%. The extraction procedure recoveries for aplidine and didemnin B were 69% and 68%, respectively in plasma and 91% and 87%, respectively in urine. Differences in linearity, LOQ, LOD and recoveries between plasma and urine samples seem to be matrix-dependent. The applicability of the method was tested by measuring aplidine in rat plasma and urine after intravenous treatment.
Celli
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G. Paone Environmental Health Center, Consorzio Mario Negri Sud, Santa Maria Imbaro, Chieti, Italy. celli@cmns.mnegri.it
Gallardo
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AM
Rossi
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C
Zucchetti
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M
D'Incalci
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M
Rotilio
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D
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D047630:Depsipeptides; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D010456:Peptides, Cyclic; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
D000970:Antineoplastic Agents; D047630:Depsipeptides; D009842:Oligopeptides; D010456:Peptides, Cyclic; C098980:plitidepsin