title: Liquid chromatography-tandem mass spectrometry evaluation of the pharmacokinetics of a diacid metabolite of norcantharidin loaded in folic acid-targeted liposomes in mice.
abstract: A previous study has reported diacid metabolite (DM) as the stable form of norcantharidin (NCTD), which is almost 100% metabolized to DM-NCTD. However, the unreliable pharmacokinetic characteristics of DM-NCTD could result in low bioavailability, hindering the clinical use of DM-NCTD in the treatment of diseases. A liposomal drug delivery system could overcome the shortcomings of DM-NCTD by improving the relative bioavailability (Fr), reducing drug toxicity, and increasing the therapeutic efficacy. However, there are no data concerning the pharmacokinetics of a DM-NCTD-loaded liposomal drug delivery system in animals, which is required for assessing its safety profile. Therefore, a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of DM-NCTD in mouse plasma. Standard curves were linear (r=0.9966) over the range 10.0-1.00×10(4)ng/ml in mouse plasma with a lower limit of quantification (LLOQ) of 10ng/ml. This study successfully investigated the pharmacokinetics of DM-NCTD and DM-NCTD encapsulated in polyethylene glycol (PEG)-Liposomes (DM-NCTD/PEG-Liposome) or folic acid (FA)-PEG-Liposomes (DM-NCTD/FA-PEG-Liposome) in Kunming mice after a single intravenous dose of 2mg/kg. The plasma profile data of the three groups adhered to a two-compartment model. Compared with the DM-NCTD group, the Liposome groups had longer circulation times following intravenous administration in mice, and the Fr of DM-NCTD increased significantly (P<0.05). Furthermore, the area under the concentration-time curve (AUC) declined with an increase in the volume of distribution (Vd) from the PEG-Liposome to the FA-PEG-Liposome groups, which indicates a more efficient removal of the drug from the plasma of the FA-PEG-Liposome group. This result suggests a possible increased risk of DM-NCTD intoxication in normal tissues with FA-PEG-Liposomes. Based on this study, further investigation of the biodistribution of DM-NCTD/FA-PEG-Liposomes in healthy animals is warranted. In addition, the plausibility of formulating a safe DM-NCTD-loaded system without increasing toxicity against normal tissues needs to be determined.
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Min-Chen
authors.initials: MC
authors.lastname: Liu
authors.affiliation: National Clinical Research Base of Traditional Chinese Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, China.
authors.forename: Xiao-Qiong
authors.initials: XQ
authors.lastname: Ma
authors.affiliation: Hubei Biological Medicine Industrial Technological Institute Co., Ltd., Wuhan 430075, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Peng
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Min
authors.initials: M
authors.lastname: Han
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: gaojianqing@zju.edu.cn.
authors.forename: Jian-Qing
authors.initials: JQ
authors.lastname: Gao
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid / Q000379:methods*; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D007275:Injections, Intravenous; D008081:Liposomes; D008297:Male; D008815:Mice, Inbred Strains; D010796:Phthalic Anhydrides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D004337:Drug Carriers; D008081:Liposomes; D010796:Phthalic Anhydrides; C035993:7-oxabicyclo(2.2.1)-5-heptene-2,3-dicarboxylic anhydride; C069741:norcantharidin; D005492:Folic Acid
keywords: Diacid metabolite of norcantharidin; Folic acid-targeted Liposome; LC–MS/MS; Mice; Pharmacokinetics