PLASMA PHARMACOKINETICS, TISSUE DISPOSITION, EXCRETION AND METABOLISMOF VINLEUCINOL IN MICE AS DETERMINED BY HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY

We investigated the pharmacokinetics of the experimental semisynthetic vinca alkaloid vinleucinol (VileE; 2-methylbutyl]amino]carbonyl]-vinc aleukoblastine). The study was performed in male FVB mice receiving 10 .5 mg/kg VileE i.v. or p.o. Plasma, urine, faeces and tissue samples w ere analysed by a selective method based on ion-exchange normal-phase high-performance liquid chromatography (HPLC) with fluorescence detect ion and liquid-liquid extraction for sample clean-up. Apart from the p arent drug, two other metabolic compounds were detected. One of these metabolites is vinleucinol acid (VileA; 2-methylbutyl]amino]carbonyl]- vincaleukoblastine), which possesses no cytotoxic activity. The struct ure proposed for the second metabolite (VileX) was based on tandem mas s spectrometry (MS-MS) and infrared (IR) spectroscopy data. Metaboliza tion of VileE to VileX must occur in the amino acid moiety of the mole cule, with a (beta or gamma-) lactone ring being formed after oxidatio n of the (beta- or gamma) carbon of the amino acid. VileX is a major m etabolite, which is excreted in faeces and urine after i.v. administra tion and accounting for up to 23% of the administered dose. The activi ty of VileX against cultured L1210 cells is four times that of the par ent drug VileE and comparable with that of vinblastine (VBL). At 48 h after administration of VileE, the concentration of VileX exceeds that of the parent drug in many tissues. These findings indicate that the metabolite VileX may be at least largely responsible for the activity observed against xenografts in mice after administration of the parent drug, VileE.