title: The integrated pharmacokinetics of major rhodojaponins correlates with the cardiotoxicity after oral administration of Rhododendri Mollis Flos extract in rats.
abstract: BACKGROUND
  Rhododendri Mollis Flos (RMF), termed as Naoyanghua in Chinese, is a traditional anti-rheumatoid arthritis and bruises herb with associated cardiotoxicity. The predominant rhodojaponins occurring in RMF are responsible for its efficacy and toxicity. The narrow therapeutic window of rhodojaponins necessitates monitoring the pharmacokinetics and pharmacodynamics so as to ensure the safety in practical applications of RMF.
  
  
  METHODS
  Fifty-four male Sprague-Dawley rats were divided into a control group, a low-dose group and a high-dose group. After oral administration of RMF extract, the cardiotoxicity of RMF was evaluated by assessing ventricular function and by measuring the plasma levels of LDH, CK-MB and AST. Then, an LC-MS method was established to determine the rat plasma concentrations of three major rhodojaponins including rhodojaponin I, II and III (R-I, II and III) and was applied to pharmacokinetic study. Finally, based on an AUC-weighting approach, the integrated pharmacokinetics of three rhodojaponins was determined.
  
  
  RESULTS
  Compared with control group, cardiotoxicity was observed in RMF-treated rats with left ventricular dysfunction and with the continuously increased levels of LDH and CK-MB in a dose-dependent manner. The pharmacokinetic parameters (AUC0-t, AUC0-∞, t1/2, Tmax and Cmax) for R-I, II and III were markedly different, and the integrated pharmacokinetics was therefore converted to describe the holistic pharmacokinetic profiles of R-I, II and III, which correlated pretty well with cardiotoxicity.
  
  
  CONCLUSIONS
  It was found that myocardial damage was elicited by RMF extract in a dose-dependent manner and the plasma levels of LDH and CK-MB could reveal the severity of myocardial injury as potential markers. This study also highlighted the potential of integrated pharmacokinetics to provid a more comprehensive understanding of the relationship between the pharmacokinetic behaviors of traditional Chinese herbal medicine and its efficacy.
authors.affiliation: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China.
authors.forename: Lei-Chi
authors.initials: LC
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China.
authors.forename: Na
authors.initials: N
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.affiliation: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tongjia Lane, Nanjing 210009, China. Electronic address: cpuli@163.com.
authors.forename: Hui-Jun
authors.initials: HJ
authors.lastname: Li
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D066126:Cardiotoxicity / Q000209:etiology*; D002853:Chromatography, Liquid; D004224:Diterpenes / Q000302:isolation & purification / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D008297:Male; D013058:Mass Spectrometry; D008516:Medicine, Chinese Traditional; D010936:Plant Extracts / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D029793:Rhododendron / Q000737:chemistry*
chemical_list: D004224:Diterpenes; D010936:Plant Extracts; C069461:rhodojaponin III
keywords: Cardiotoxicity; Integrated pharmacokinetics; LC–MS; Rhododendri Mollis Flos; Rhodojaponins