| Autor: |
Embree, Leanne, Gelmon, Karen A., Lohr, Andreas, Mayer, Lawrence D., Coldman, Andrew J., Cullis, Pieter R., Palaitis, Waldemar, Pilkiewicz, Frank, Hudon, Norma J., Heggie, Jean R., Goldie, James H. |
| Zdroj: |
Journal of Pharmaceutical Sciences; June 1993, Vol. 82 Issue: 6 p627-634, 8p |
| Abstrakt: |
A sensitive and specific quantitative assay for total doxorubicin concentrations in plasma containing liposome-encapsulated doxorubicin hydrochloride (TLC D-99) was developed, with solvent extraction and reversed-phase high-performance liquid chromatography (HPLC). Separation of doxorubicin from its metabolites was accomplished with a 15 cm x 3.9mm i.d., μBondapak phenyl analytical HPLC column. Optimum chromatographic conditions, obtained with a mobile phase gradient from 85 to 50% (v/v) 16mM ammonium formate buffer in tetrahydrofuran at a flow rate of 2 mL/min, gave a detection limit of 0.3 pmol/injection. Eleven-point standard curves with from 0.00595 to 29.8 μM TLC D-99 and 0.1 μMinternal standard in plasma were analyzed on three separate occasions to formally validate this assay. An overall correlation coefficient of 0.9985 was found for the logarithmic transformed data. The pharmacokinetic characteristics of doxorubicin were investigated after administration of TLC D-99 to 12 non-small-cell lung cancer patients as an intravenous infusion at doses of 60 and 75 mg/m2. The data are best described by a three-compartment model with ɑ, β,and γelimination half-lives of 0.0721,2.84, and 25.2h for the 60-mg/m2group and 0.103, 2.56, and 14.9h for the 75-mg/m2patients. A mean plasma clearance of 9.89 L/h (range: 1.95 to 23.4 L/h) was found for the 60-mg/m2patients, with that from the 75-mg/m2group being within these values. Mean area under the plasma concentration versus time curve estimates of 37.1 and 47.9 μM/h were observed for the patients receiving 60 and 75 mg/m2, respectively. The plasma concentration-time course for total doxorubicin following administration of TLC D-99 suggests that the disposition of the liposomal formulation is determined more by the pharmacokinetics of the liposome than the encapsulated drug. |
| Databáze: |
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