Comparison of tumor pharmacokinetics of free doxorubicin versus liposomal formulations of doxorubicin
| Formulation . | Doxil (16 mg/kg) . | . | Doxil (9 mg/kg) . | . | DOPC-PLD (9 mg/kg) . | . | Free doxorubicin (9 mg/kg) . | . | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| . | Total . | Nuclear . | Total . | Nuclear . | Total . | Nuclear . | Total . | Nuclear . | ||||
| AUC (μeq h/g tumor) | 5,918 | 2,444 | 3,988 | 1,970 | 641 | 172 | 45.8 | 43.3 | ||||
| % Bioavailable | 41.3% | 49.4% | 26.8% | 95.1% | ||||||||
| Cmax (μeq doxorubicin/g tumor) | 48.8 | 25 | 28.6 | 15.9 | 11.9 | 11.4 | 7.9 | 2.9 | ||||
| Tmax (h) | 48 | 96 | 24 | 96 | 12 | 4 | 0.5 | 4 | ||||
| t1/2 (h) | 135 | ND | 151 | ND | 78 | ND | 25 | ND | ||||
| MRT (h) | 81 | ND | 81 | ND | 52 | ND | 10 | ND | ||||
| Clearance (g/h/kg) | 1.5 | ND | 1.1 | ND | 11.3 | ND | 89 | ND | ||||
| Formulation . | Doxil (16 mg/kg) . | . | Doxil (9 mg/kg) . | . | DOPC-PLD (9 mg/kg) . | . | Free doxorubicin (9 mg/kg) . | . | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| . | Total . | Nuclear . | Total . | Nuclear . | Total . | Nuclear . | Total . | Nuclear . | ||||
| AUC (μeq h/g tumor) | 5,918 | 2,444 | 3,988 | 1,970 | 641 | 172 | 45.8 | 43.3 | ||||
| % Bioavailable | 41.3% | 49.4% | 26.8% | 95.1% | ||||||||
| Cmax (μeq doxorubicin/g tumor) | 48.8 | 25 | 28.6 | 15.9 | 11.9 | 11.4 | 7.9 | 2.9 | ||||
| Tmax (h) | 48 | 96 | 24 | 96 | 12 | 4 | 0.5 | 4 | ||||
| t1/2 (h) | 135 | ND | 151 | ND | 78 | ND | 25 | ND | ||||
| MRT (h) | 81 | ND | 81 | ND | 52 | ND | 10 | ND | ||||
| Clearance (g/h/kg) | 1.5 | ND | 1.1 | ND | 11.3 | ND | 89 | ND | ||||
NOTE: Tumor levels of total doxorubicin and nuclear doxorubicin were determined in mice bearing orthotopic 4T1 mammary carcinomas following administration of 9 mg/kg doxorubicin as Doxil, DOPC-PLD, or free doxorubicin. Some mice also received 16 mg/kg of Doxil. AUC0-24 h for free doxorubicin and AUC0- 7d for liposomal doxorubicin formulations. All variables were determined using WinNonLin software.
Abbreviations: ND, no value determinable by the pharmacokinetic program; DOPC-PLD, dioleoylphosphatidylcholine/CHOL/mPEG2000-DSPE; MRT, mean residence time; μeq, microequivalents.