Pharmacokinetics and tissue distribution of vinorelbine delivered in parenteral lipid emulsion

Abstract

AbstractThe pharmacokinetics and biodistribution of vinorelbine (VRB) delivered in a parenteral lipid emulsion (VLE) were evaluated, and compared with that of a commercial vinorelbine injectable solution (Navelbine® i.v., VS). After intravenous administration to rats at doses of 2.25, 4.5, and 9 mg/kg, the AUC0–24 h was significantly different (1.15 ± 0.27, 2.65 ± 0.82, and 8.18 ± 1.10 mg/L/h for 2.25, 4.5, and 9 mg/kg, respectively), other pharmacokinetic parameters of VLE, such as the Cmax, CL, and Vss, were also dependent on the dose of VLE. The pharmacokinetics of VLE in rats was dose‐dependent in the dosage range of 2.25–9 mg/kg. VLE exhibited significantly higher VRB concentration than that of VS at the initial time points, it also produced a higher AUC0–24 h, MRT and lower CL in comparison with VS. In beagle dogs, VLE exhibited pharmacokinetic bioequivalence to VS. The tissue distribution in mice of VLE was modified compared to VS, the AUC0–48 h of VLE was grater in the liver, spleen, kidney and small intestine, but a little lower in the heart and lung.Practical applications: To reduce the severe local venous irritation of vinorelbine (VRB) at the aim of improve patient compliance, a parenteral vinorelbine loaded lipid emulsion (VLE) has been developed, and then systematical preclinical evaluations have been done. The pharmacokinetics and tissue distribution study reported here are part of the preclinical evaluation. VLE exhibited non‐linear relationship between dose and AUC0–24 h after single intravenous dose (at doses of 2.25, 4.5, and 9 mg/kg) to rats. Pharmacokinetic bioequivalence between VLE and VS was found after single intravenous infusion administration a dose of 1.33 mg/kg to beagle dogs. Tissue distribution results showed that the AUC0–48 h of VLE was grater in the liver, spleen, kidney, and small intestine, but a little lower in the heart and lung. These results could provide information for the further pharmacodynamics and pharmacology study, and finally for clinical use of VLE.