9 mL/min/kg). Accordingly, plasma AUC0-8 was approximately 40-fold less with nanosuspension delivery (Table 1). Tumor concentrations (Figures 3 and 4) and exposures (Table 1) were higher for selleck chemicals llc Cremophor EL:ethanol delivery with AUC0-8 being approximately 3-fold higher compared to nanosuspension delivery. In contrast, click here paclitaxel liver concentrations (Figures 3 and 4) and exposures (Table 1) were higher for nanosuspension
delivery with AUC0-8 being approximately 6-fold higher than that observed for the Cremophor EL:ethanol formulation. Spleen exposure was comparable for the two formulations (Table 1). Figure 3 Paclitaxel concentration-time profile in plasma, tumor, liver, and spleen following intravenous administration using Cremophor EL:ethanol formulation. Figure 4 Paclitaxel concentration-time profile in plasma, tumor, liver, and spleen following intravenous administration using nanosuspension formulation. Table 1 Exposure (mean value) of paclitaxel in plasma, see more tumor, liver, and spleen following intravenous administration
Tissue AUC0-8(μM × h) Formulation Cremophor EL:ethanol Nanosuspension Plasma 74.7 2.1 Tumor 52.1 17.5 Liver 269.1 1,701.1 Spleen 85.2 147.5 Paclitaxel tissue to plasma ratios were determined in order to assess formulation-dependent differences in tissue distribution in tumor, spleen, and liver (Table 2). Delivery with nanosuspension resulted in higher tissue to plasma ratios for all Pyruvate dehydrogenase lipoamide kinase isozyme 1 three organs investigated (Figure 5, Table 2). In particular, the liver to plasma
ratio was exceptionally high being approximately 225-fold higher with nanosuspension delivery. Table 2 Tissue to plasma exposure ratio of paclitaxel for tumor, liver, and spleen following intravenous administration Tissue to plasma ratio Formulation Cremophor EL:ethanol Nanosuspension Tumor AUC0-8/plasma AUC0-8 0.7 8.3 Liver AUC0-8/plasma AUC0-8 3.6 810.0 Spleen AUC0-8/plasma AUC0-8 1.1 16.8 AUC0-8, area under the concentration-time profile from 0 to 8 h. Figure 5 Log tissue to plasma ratios for tumor, liver, and spleen following intravenous delivery to mice. Anti-tumor efficacy of paclitaxel In order to compare the relative efficacy of Cremophor EL:ethanol versus nanosuspension delivery, percent tumor growth inhibition was determined at the end of the study. Delivery of paclitaxel with the standard Cremophor EL:ethanol formulation resulted in 90% TGI (Figure 6). The use of nanosuspension for intravenous delivery resulted in considerably less efficacy with TGI being 42%. Figure 6 Plots of mean tumor volume versus time in xenograft mice for intravenous paclitaxel. In order to normalize the anti-tumor efficacy with differences in paclitaxel exposure observed with the two formulations, TGI was normalized with respect to the plasma and the site of action (i.e., tumor). Figure 7 shows normalized efficacy with respect to plasma and tumor exposures for both formulations.
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