Doxorubicin plasma levels

Further investigations revealed that the superior antitumor efficacy of Leu-DOX was, indeed, due to site-selective activation and delivery of doxorubicin. At equitoxic intravenous doses of DOX and Leu-DOX (8 and 28 mg/kg, respectively, see above), the plasma levels of DOX attained were comparable, whereas differences were seen in tumor tissue concentrations [51]. The enzymes involved in the tumor-selective activation of Leu-DOX were not identified, although possible candidates include the cathepsin family of proteases [47],... 

The pharmacokinetics fCD and HlftCD after intravenous administration have been assessed (Frijlinket al., 1990). As determined at doses of 25,100, and 200 mg/kg in permanently cannulated rats, plasma levels of both CDs decreased rapidly upon injection. Within 24 h after administration, most of the doses were excreted unchanged via urine. There was no evidence forsigniLcant metabolism of the intravenously administered CDs. The pharmacokinetics and the tissue concentrations of methyl-p-cyclodextrin (MEBCD) and doxorubicin (DOX) in rabbits following administration of MEBCD and DOX, alone or in combination were studied (Grosse et al., 1999). Results indicated that DOX did not modify MEBCD pharmacokinetic proLle, but MEBCD reduced signiLcantly the distribution half-life of DOX. Tissue determination showed that MEBCD did not enhanced the cardiac accumulation of DOX. 

Oral verapamil has been shown to increase peak plasma levels, prolong the terminal half-life, and increase the volume of distribution at steady state of doxorubicin (282). Gigante et al. (283) performed similar studies in which the pharmacokinetics of doxorubicin in combination with verapamil given at high doses intravenously were followed for 17 patients with advanced neoplasms. The steady-state concentration and systemic and renal clearances were found to be statistically similar for various doses of verapamil and doxorubicin, and for doxorubicin administered alone. 

On the other hand, alteration of the drug distribution profile by linkage to nanospheres can, in some cases, considerably reduce the toxicity of a drug because of reduced accumulation in organs where the most acute toxic effects are exerted. This concept was indeed illustrated with doxorubicin, which displays severe acute and chronic cardiomyopathy. After intravenous administration to mice, plasma levels of doxorubicin were higher when the drug was adsorbed onto nanospheres and at the same time the cardiac concentration of the drug was dramatically reduced. In accordance with the observed distribution profile, doxorubicin associated with nanospheres was found to be less toxic than free doxorubidn. ... 

In 10 patients the AUC of intravenous pegylated liposomal doxorubicin (Caelyx) 30 to 35 mg/m was increased by a mean of 80% when it was given with intravenous paclitaxel 70 or 175 mg/m. Peak plasma levels of doxorubicin were also increased and clearance was reduced by 71%. In 9 other patients given Caelyx with docetaxel 30 or 60 mg/m, the AUC of doxorubicin was increased by 12% and clearance reduced by only 16%. ... 

Other drags that suppress hver CYP2C11 and CYP3A2 levels include cyclosporine [203, 204] and chloramphenicol [205], although the latter effects are strain dependent and are associated with a modest reduction in plasma levels of thyroxine but not testosterone [205]. GH does not appear to play a role in the suppression of CYP2C11 and CYP3A2 by cyclosporine, which does not alter the plasma GH peak amplitude, niunber, or duration [206]. Phenobarbital [24, 207, 208], dexa-methasone [28], 5-fluoroiuacil [209], doxorubicin [210], fenofibrate [211], rosuvastatin [212],... 

Daunorubicin and doxorubicin are eliminated by metabolic conversion to a variety of aglycones and other inactive products. Idarubicin is primarily metabolized to idarubicinol, which accumulates in plasma and likely contributes significantly to its activity. Clearance is delayed in the presence of hepatic dysfunction, and at least a 50% initial reduction in dose should be considered in patients with abnormal serum bilirubin levels. 

Daunorubicin, doxorubicin, epirubicin, and idarubicin usually are administered intravenously. Careful infusion over 10-15 minutes is recommended to prevent extravasation, since severe local vesicant action may result. The drugs are cleared by a complex pattern of hepatic metabolism and biliary excretion. The plasma disappearance curve for doxorubicin is multipha-sic, with elimination half-lives of 3 hours and - SO hours. All anthracyclines are converted to an active alcohol intermediate that plays a variable role in their therapeutic activity. Idarubicin has a tj of 15 hours, and its active metabolite, idarubicinol, has a tj of - 40 hours. There is rapid upt e of the drugs in the heart, kidneys, lungs, liver, and spleen. They do not cross the blood-brain barrier. Daunorubicin and doxorubicin are eliminated by metabolic conversion to a variety of aglycones and other inactive products. Idarubicin is primarily metabolized to idarubicinol, which accumulates in plasma and likely contributes significantly to its activity. Clearance is delayed in the presence of hepatic dysfunction, and at least a 50% initial reduction in dose should be considered in patients with elevated serum bilirubin levels. 

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