| Honokiol,is a biphenolic compound isolated and purified from the root,stem bark and the seeds cones ofMagnolia officinalis Rehd.et Wils(Houpu in Chinese).Previous studies have shown that honokiol has strong anti-tumor activities against non-small cell lung cancer,including H460,SPC-Al,HCC827 and H1975 so on.Honokiol may be a potential candidate for lung cancer therapy in the near future and in the clinical research and development stage.Based on the previous experiment,this paper research the preclinical toxicokinetics in Beagle dogs and metabolites in rat kidney by means of UHPLC-MS/MS and UHPLC-Q-TOF/MS/MS.The main contents are as follows:1.A method has been developed for the determination of honokiol in plasma samples of Beagle dogsA rapid,sensitive liquid chromatography-tandem mass spectrometry method was developed for quantitation of honokiol in plasma samples of Beagle dogs.The results of method validation suggested that the specific,sensitivity,accuracy and repeatability all met the general criteria for biological sample analysis methods.So this method was employed to quantitative analysis of honokiol in plasma samples of Beagle dog.2.Beagle dogs intravenous infusion of honokiol liposome 4 weeks toxicokinetic studyA total of 50 Beagle dogs(half male and half female)were randomly divided into five groups(for collecting samples after first and last time drug administration)respectively.Honokiol liposome in low,middle,high dose groups,negative control and blank liposome groups with 10 Beagle dogs in each group.Administrating one times daily for continuously four weeks.Blood samples collected at different time points in the first and after the last administration,and then was analyzed by UHPLC-MS/MS.Cmax and AUC(0-t)for the the first time and last time after administration were compared,statistical results showed that there was significant difference in the low.middle and high dose groups,the first Cmax value of the ratio were 0.77,1.22,0.77 respectively,AUC(0-t)ratio were 0.99,1.25,0.70 respectively.Low dose group and high dose group at the time of the last and for the first time after administration of Cmax and AUC(0-t)ratios were less than 1,the middle dose group after administration for the first time last with Cmax and AUC(0-t)ratio was larger than 1,after repeated administration,the honokiol exposure level that low dose group and high dose group in Beagle dogs in vivo did not increase,the level of exposure dose of honokiol was gradually increased.At the end of each dose group and for the first time after administration of Cmax and AUC(0-t)ratio showed that,at 4 mg/kg,12 mg/kg and 40 mg/kg dose group,almost no accumulation.Honokiol in 4～40 mg/kg dose range has linear pharmacokinetics.3.Identification of metabolites of honokiol in rat kidney in vivoKidneys are an important organ since they make a significant contribution to the metabolism and excretion of drugs in vivo.The purpose of this study was to identity and tentatively elucidate honokiol metabolites in the rat kidney,after healthy rats were exposed to a 1:1 mixture of labeled 13C-honokiol and unlabeled honokiol,by ultra high performance liquid chromatography coupled with a quadrupole time-of-flight mass spectrometer platform.This platform is well known for its fast acquisition speed,superior sensitivity,high resolution,and excellent mass accuracy.Finally,a total of 19 metabolites belonging to phase Ⅱ metabolites were identified tentatively by exact mass,and the fragmentation spectra of four metabolites are reported for the first reported time.Our results indicated that honokiol was metabolized via phase Ⅱbiotransformation including sulfation,acetylation,glucuronidation and amino acid conjugation in rat kidney tissues.This is the first study focused on the honokiol biotransformation in the tissue of kidney,providing important details for a comprehensive standing of the metabolites of honokiol. |
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