Metabolism and excretion of paclitaxel after oral administration in combination with cyclosporin A and after i.v. administration

Abstract

The objective of this study was to compare the quantitative excretion of paclitaxel and metabolites after i.v. and oral drug administration. Four patients received 300 mg/m2 paclitaxel orally 30 min after 15 mg/kg oral cyclosporin A, co-administered to enhance the uptake of paclitaxel. Three weeks later these and three other patients received 175 mg/m2 paclitaxel by i.v. infusion. Blood samples, urine and feces were collected up to 48-96 h after administration, and analyzed for paclitaxel and metabolites. The area under the plasma concentration-time curve of paclitaxel after i.v. administration (175 mg/m2) was 16.2 +/- 1.7 microM x h and after oral administration (300 mg/m2) 3.8 +/- 1.5 microM x h. Following i.v. infusion of paclitaxel, total fecal excretion was 56 +/- 25%, with the metabolite 6alpha-hydroxypaclitaxel being the main excretory product (37 +/- 18%). After oral administration of paclitaxel, total fecal excretion was 76 +/- 21%, of which paclitaxel accounted for 61 +/- 14%. In conclusion, after i.v. administration of paclitaxel, excretion occurs mainly in the feces with the metabolites as the major excretory products. Orally administered paclitaxel is also mainly excreted in feces but with the parent drug in highest amounts. We assume that this high amount of parent drug is due to incomplete absorption of orally administered paclitaxel from the gastrointestinal tract.

Population pharmacokinetics of orally administered paclitaxel formulated in Cremophor EL

“…Owing to the distribution of CrEL micelles over the gastrointestinal tract wall, and the degradation and elimination of micelles with time, paclitaxel may be liberated and then absorbed in the circulation. This may be explained by (1) dilution of micelles in the gastrointestinal tract by increasing the contact surface area and to concentrations lower than the critical micellar concentration (which appeared to be 0.33% w/v in the small intestine of mice [20]) or (2) degradation of CrEL, since it has been shown that only 32% of administered CrEL is recovered in faeces [30]. The amount of CrEL in the hypothetical compartment in our semimechanistic model approached zero within approximately 5 h after administration.…”

Enhanced Oral Delivery of Docetaxel Using Thiolated Chitosan Nanoparticles: Preparation, In Vitro and In Vivo Studies

“…Thiolated chitosan nanoparticles when administered orally could enhance oral bioavailability of DTX instead of current regimen of chemotherapy (IV injection). In addition, it can be regarded as a superior system when compared to other strategies that use P-gp/P450 inhibitors like cyclosporine-A with many side effects [11, 12]. …”

“…High concentration of solubilizers in its formulation causes toxic effects and allergic reactions [10]. Various methods have been suggested to overcome these problems such as applying a P-gp/P450 inhibitor such as cyclosporine A [11, 12], formulated as liposomes [13, 14], emulsions [15, 16], polymeric nanoparticles [17–21], and conjugation of DTX with water soluble polymers [22, 23]. …”

Nanomedicine: New Challenges and Opportunities in Cancer Therapy

“…This molecule has less than 10% oral bioavailability in conventional formulations, 66 because most of the drug is eliminated through the cytochrome P450-dependent metabolism, and excreted by the P -glycoprotein (P -gp) pump present in the intestinal wall. [66][67][68][69][70] Indeed, the bioavailability of this drug can be improved by the addition of P -gp inhibitors, such as cyclosporine A, to the formulation. [71][72][73] Nanosystems may improve drug absorption in oral chemotherapy by protecting the drug, enhancing its residence time at the absorption site, or through the inhibition of efflux pumps.…”