Abstract
So far, all animal pharmacokinetic studies of paclitaxel, which used analytical procedures based on HPLC, have not been sensitive enough to quantify drug levels below 500 ng/ml. Consequently, the interpretation of the results is restricted because drug levels of paclitaxel as low as at least 50 nM (43 ng/ml) are relevant for the pharmacology of this drug. We recently described an accurate and very sensitive method based on HPLC for the determination of paclitaxel and the metabolites 3'-p-hydroxypaclitaxel (I), 6 alpha-hydroxypaclitaxel (II) and 6 alpha,3'-p-dihydroxypaclitaxel (III) in a wide variety of biological matrices. We have now implemented this methodology in a comprehensive pharmacokinetic study in female FVB mice. Previous pharmacokinetic studies in humans demonstrated a large steady-state volume of distribution, indicating that the drug is widely distributed into tissues. Comprehensive tissue distribution studies may, therefore, be helpful in providing more insight into possible relationships between plasma levels, drug levels in tissues and toxicity. Paclitaxel, formulated in Cremophor EL and ethanol (1:1, v/v), was given as a single i.v. bolus dose of 2, 10 and 20 mg/kg to female FVB mice. Except for the brain, the distribution of paclitaxel to all other tissues in the female mice was substantial and maximum drug levels were achieved within 0.5 or 1 h. A marked non-linear increase in the area under the concentration-time curve (AUC) in plasma was observed, which was not paralleled by a proportional increase in the tissue AUC levels. It is postulated that this effect may be related to the substantial amounts of Cremophor EL administered concurrently. The recovery of paclitaxel in the feces (0-96 h) was reduced from 58% at the 2 mg/kg dose level to 44% at the 20 mg/kg dose level. Small amounts of metabolites I and II were detected in the gut, liver and gall bladder, but not in the systemic circulation or any other tissue. Metabolite III was not detected. Metabolites I and II are likely excreted directly into the bile, and since their recovery in the feces accounts for about 25% of the administered dose, their formation thus represents an important pathway of detoxification.