Pharmacokinetics, tissue distribution, and metabolites of a polyvinylpyrrolidone-coated norcantharidin chitosan nanoparticle formulation in rats and mice, using LC-MS/MS

Xin-Yuan Ding¹, Cheng-Jiao Hong², Yang Liu¹, Zong-Lin Gu¹, Kong-Lang Xing¹, Ai-Jun Zhu¹, Wei-Liang Chen¹, Lin-Seng Shi¹, Xue-Nong Zhang¹, Qiang Zhang<sup>3

1</sup>Department of Pharmaceutics, College of Pharmaceutical science, Soochow University, Suzhou, ²Jiang Su Provincial Key Laboratory of Radiation Medicine and Protection, Suzhou, ³Department of Pharmaceutics, School of Pharmaceutical Science, Peking University, Beijing, People’s Republic of China

Abstract: A novel formulation containing polyvinylpyrrolidone (PVP) K₃₀-coated norcantharidin (NCTD) chitosan nanoparticles (PVP–NCTD–NPs) was prepared by ionic gelation between chitosan and sodium tripolyphosphate. The average particle size of the PVP–NCTD–NPs produced was 140.03 ± 6.23 nm; entrapment efficiency was 56.33% ± 1.41%; and drug-loading efficiency was 8.38% ± 0.56%. The surface morphology of NCTD nanoparticles (NPs) coated with PVP K₃₀ was characterized using various analytical techniques, including X-ray diffraction and atomic force microscopy. NCTD and its metabolites were analyzed using a sensitive and specific liquid chromatography-tandem mass spectrometry method with samples from mice and rats. The results indicated the importance of the PVP coating in controlling the shape and improving the entrapment efficiency of the NPs. Pharmacokinetic profiles of the NCTD group and PVP–NCTD–NP group, after oral and intravenous administration in rats, revealed that relative bioavailabilities were 173.3% and 325.5%, respectively. The elimination half-life increased, and there was an obvious decrease in clearance. The tissue distribution of NCTD in mice after the intravenous administration of both formulations was investigated. The drug was not quantifiable at 6 hours in all tissues except for the liver and kidneys. The distribution of the drug in the liver and bile was notably improved in the PVP–NCTD–NP group. The metabolites and excretion properties of NCTD were investigated by analyzing rat feces and urine samples, collected after oral administration. A prototype drug and two metabolites were found in the feces, and seven metabolites in the urine. The primary elimination route of NCTD was via the urine. The quantity of the parent drug eliminated in the feces of the PVP–NCTD–NP group, was 32 times greater than that of the NCTD group, indicating that the NPs dramatically increased the reduction quantity from liver to bile. We conclude that PVP–NCTD–NPs are an adequate formulation for enhancing the absorption of NCTD, and significantly improving therapeutic effects targeting the hepatic system. Decarboxylation and hydroxylation were the dominant metabolic pathways for NCTD. Metabolites were mainly excreted into rat kidney and finally into urine.

Keywords: pharmacokinetics, metabolites, NCTD, PVP, LC-MS/MS