Intravenous Administration of Paclitaxel in Sprague-Dawley Rats: What is a Safe Dose?

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Abstract

Few studies describe the administration of TaxolTM to rats; however, rats are typically used to study the toxicity of new drugs or novel formulations. A dose finding study was conducted to determine a safe dose of TaxolTM following intravenous administration in rats. Male Sprague-Dawley rats received a bolus of paclitaxel 5–20 mg/kg i.v. Blood was drawn before administration and at the following times after administration: 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20 and 24 h. Plasma concentrations were determined using high performance liquid chromatography. Two rats received paclitaxel 20 mg/kg and died immediately. Nine rats received paclitaxel 10 mg/kg; seven of these rats died within 12 h and two rats were killed due to moribund conditions. Ten rats received paclitaxel 5 mg/kg with no morbidity. The following pharmacokinetics for paclitaxel in the plasma were estimated: C0, 8977 ng/ml; AUC0→∞, 7477 ng*h/ml; CLs, 668 ml/h*kg; Vss, 1559 ml/kg; Vz 2557 ml/kg and t1/2, 2.6 h. It is concluded that further pharmacokinetic studies that are rationally designed to include appropriate measures of preclinical toxicity associated with paclitaxel are needed to identify formally the safest dose in rats following intravenous administration; however, these data indicate that male Sprague-Dawley rats can safely receive TaxolTM in a 5 mg/kg i.v. bolus. Copyright © 2006 John Wiley & Sons, Ltd.

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