Paclitaxel in self-micro emulsifying formulations: oral bioavailability study in mice

Area of Science:

• Pharmacology
• Drug Delivery
• Gastroenterology

Background:

• Paclitaxel, an anticancer drug, has poor oral bioavailability due to P-glycoprotein and CYP450 activity.
• Current intravenous formulations require co-administration with inhibitors for oral efficacy.
• Existing oral solutions have undesirable pharmaceutical properties, necessitating improved formulations.

Purpose of the Study:

• To evaluate self-micro emulsifying oily formulations (SMEOF) for oral paclitaxel delivery.
• To assess the role of P-glycoprotein and CYP450 inhibition in oral paclitaxel bioavailability using SMEOF.
• To compare SMEOF performance with existing oral formulations.

Main Methods:

• Paclitaxel was formulated into various SMEOF.
• Studies were conducted in wild-type and P-glycoprotein knockout mice.
• Cyclosporin A (CsA) was used as a P-glycoprotein and CYP450 inhibitor.
• Oral paclitaxel bioavailability was assessed by measuring plasma levels and fecal excretion.

Main Results:

• SMEOF alone did not enhance oral paclitaxel bioavailability in wild-type mice.
• Paclitaxel in SMEOF#3 with CsA achieved plasma levels comparable to the Cremophor EL/ethanol solution with CsA.
• AUC increased linearly with dose in knockout mice, but less proportionally in wild-type mice with CsA, suggesting dose-dependent precipitation and metabolism saturation.

Conclusions:

• SMEOF show potential as oral delivery vehicles for paclitaxel when co-administered with inhibitors like CsA.
• Physical stability of SMEOF in the gastrointestinal tract is a critical concern, particularly at higher paclitaxel doses.
• Further research is needed to optimize SMEOF for stable and effective oral paclitaxel delivery.