Vinca Alkaloid Skin Toxicity: Antidote and Drug Disposition Studies in the Mouse23

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Abstract
A murine (BALB/c) skin toxicity model was used to evaluate various possible antagonists to vinca alkaloid-induced skin ulceration. Reproducible dose-response relationships were developed for vinblastine (VBL) and vindesine (VDS). With vincristine (VCR) only about 70% of mice developed dose-dependent ulceration. On an equal weight basis, VCR proved to be significantly more toxic than either VBL or VDS (P<.05 by Student's t-test). Effective local intradermal antidotes to VBL, VDS, and VCR included hyaluronidase, normal saline, and calcium leucovorin (P<.05 by the Student's Newman-Keuls multiple range test). Mild, topical skin heating significantly reduced VCR ulceration. In contrast, diphenhydramine and sodium bicarbonate were ineffective as local antidotes. Topical skin cooling, however, significantly increased vinca-induced skin ulcers for VBL, VDS, and VCR (P<.05). Hydrocortisone, vitamin A topical cream, and isoproterenol increased skin toxicity. [3H]VBL was given intradermally to follow the drug's pharmacokinetic disposition from the skin and adherent panniculus carnosus muscle. [3H]VBL exhibited two phases of elimination: a rapid early phase [half-life (t½) of ≈30 min] and a prolonged terminal phase (t½ of ≈17 hr). The application of heat increased the distributive, early phase by 0.5–2.5 hours and did not enhance the terminal elimination of the drug from skin. Intradermal hyaluronidase significantly reduced the area under the ulceration multiplied by the time curve to one-seventh the control value, the peak [3H]VBL skin concentration to one-half the control value and the terminal [3H]VBL t½ in skin to one-third the control level (P<.05 by Student's t-test). These results show hyaluronidase to be an effective antidote for vinca-induced skin ulceration. Local glucocorticosteroids and topical cooling are definitely contraindicated in the management of inadvertent vinca alkaloid extravasations.