Drug distribution and a pulmonary adverse effect of intraperitoneally administered doxorubicin niosomes in the mouse

Abstract

Niosomes (non-ionic surfactant vesicles) prepared from C₁₆G₂ (a hexadecyl-diglycerol ether), and loaded with doxorubicin, were administered intraperitoneally to male AKR mice at dose levels of 0, 2.5, 5.0, and 10.0 mg kg⁻¹. Free drug was given at 10.0 mg kg⁻¹ by the intraperitoneal route. At a dose level of 10.0 mg kg⁻¹, peak doxorubicin levels in the central compartment were attained faster with the free drug than with the niosome formulation. However, the peak plasma levels were similar for the free drug and the niosome preparation at the 10 mg kg⁻¹ dose level. With doxorubicin administered as the niosome preparation by the intraperitoneal route at 2.5, 5.0, and 10.0 mg kg⁻¹, mean peak plasma concentrations of the drug showed a tendency to be dose-related although the differences were not significant. Over the 24 h period of the experiment, with doxorubicin at 10 mg kg⁻¹, the niosome formulation delivered significantly more drug to the plasma compartment than the free drug (p −1 by the intraperitoneal route, the resulting levels of doxorubicin in cardiac tissue were not dose related and the differences not significant and, although the mean peak cardiac-tissue concentration was higher in animals receiving the free drug at 10.0 mg kg⁻¹ intraperitoneally than in mice given intaperitoneal doxorubicin niosomes at this dose level, the differences were again not significant. There were clinical signs of toxicity in mice given doxorubicin-containing niosomes intraperitoneally at 5.0 and 10.0 mg kg⁻¹, and at post-mortem an accumulation of fluid in the pleural cavity was evident. These changes were not seen in mice dosed intraperitoneally with free drug at 10 mg kg⁻¹, or in animals given doxorubicin niosomes intraperitoneally at 2.5 mg kg⁻¹. In mice dosed intraperitoneally with doxorubicin niosomes at 12.0 mg kg⁻¹ and at a dose volume of 0.2–0.4 mL, histological examination of the lungs demonstrated a congestion of the alveolar capillaries, and an increased number of acute inflammatory cells in the alveolar walls. There was no histological evidence of lung toxicity in mice dosed with doxorubicin niosomes at 12.0 mg kg⁻¹ when the formulation was administered with the higher dose volume of 1.8–2.0 mL. Importantly there was no histological evidence of lung toxicity in mice dosed with empty niosomes intraperitoneally or with doxorubicin niosomes given itravenously at 12.0 mg kg⁻¹.