title: Andrographis paniculata: Dissolution investigation and pharmacokinetic studies of four major active diterpenoids after multiple oral dose administration in healthy Thai volunteers.
abstract: BACKGROUND
  Andrographis paniculata is included in 'The National List of Essential Herbal Drugs A.D. 1999' of Thailand as an herbal drug for the treatment of common cold symptoms and non-infectious diarrhea. The therapeutic activities of A. paniculata are attributed to four major active diterpenoids: andrographolide (1), 14-deoxy-11, 12-didehydroandrographolide (2), neoandrographolide (3), and 14-deoxyandrographolide (4). However, the pharmacokinetic studies in humans of this plant were performed after a single oral dose administration and reported the parameters related to be of only 1.
  
  
  OBJECTIVE
  This study aims to determine the pharmacokinetic parameters of four major active diterpenoids after multiple oral dose administration of A. paniculata capsules in healthy volunteers. The dissolution testing of these four diterpenoids was also performed.
  
  
  METHODS
  The dissolution testing of four major active diterpenoids was conducted in pH 1.2, pH 4.5, and pH 6.8 for 10-100min. The pharmacokinetic study of these active diterpenoids was designed as an open-label, multiple oral dose administration of A. paniculata capsules in 20 healthy Thai volunteers at 1:1 ratio of female and male. Each volunteer was given four A. paniculata capsules each time which contained 1, 2, 3, and 4 in the quantities of 32.64, 5.40, 3.60, and 3.84mg, respectively, three times a day for three consecutive days. On the fourth day, after the first dose of the day was administered, blood samples were collected at the predefined time points. The validated LC-MS/MS method was used to simultaneously determine the concentrations of these diterpenoids in the human plasma samples. The pharmacokinetic parameters of each active diterpenoid were determined.
  
  
  RESULTS
  All four major active diterpenoids have been completely dissolved in the simulated pH of gastrointestinal tract within 60min of dissolution. The dissolution profiles were found to be highest in pH 6.8 and lowest in pH 1.2, especially for 3. In the pharmacokinetic study, although 1 was administered at the highest dose among these four diterpenoids, 2 exhibited the highest maximum concentrations (Cmax) of 44.89ng/mL and area under the plasma concentration-time curve (AUC) of 128.17h×ng/mL. Compound 1 had the second highest Cmaxand AUC as 32.41ng/mL and 55.23h×ng/mL, respectively. The relative systemic exposure, represented by the dose normalized AUC [(h×ng/mL)/(mg/kg)], of 2 was approximately 14 times higher than that of 1, while those of 3 and 4 were approximately 1.5 and 1.6 times higher, respectively. Cmax, AUC, apparent volume of distribution, and apparent clearance of 2 were found to be significant difference between female and male. However, when these parameters were calculated as dose normalized basis, no statistically significant difference was found.
  
  
  CONCLUSIONS
  The four major active diterpenoids in the A. paniculata capsules were soluble in all studied dissolution media. The pharmacokinetic parameters of these active diterpenoids in the present study could be applied for dose optimization of A. paniculata product in order to obtain good therapeutic efficacy and reduce the possible side effects that may occur from different active diterpenoids in this medicinal plant.
authors.affiliation: Laboratory of Pharmacology, Chulabhorn Research Institute, Bangkok 10210, Thailand.
authors.forename: Nanthanit
authors.initials: N
authors.lastname: Pholphana
authors.affiliation: Translational Research Unit, Chulabhorn Research Institute, Bangkok 10210, Thailand.
authors.forename: Duangchit
authors.initials: D
authors.lastname: Panomvana
authors.affiliation: Laboratory of Pharmacology, Chulabhorn Research Institute, Bangkok 10210, Thailand; Environmental Toxicology Program, Chulabhorn Graduate Institute, Bangkok 10210, Thailand.
authors.forename: Nuchanart
authors.initials: N
authors.lastname: Rangkadilok
authors.affiliation: Laboratory of Pharmacology, Chulabhorn Research Institute, Bangkok 10210, Thailand.
authors.forename: Tawit
authors.initials: T
authors.lastname: Suriyo
authors.affiliation: Translational Research Unit, Chulabhorn Research Institute, Bangkok 10210, Thailand.
authors.forename: Porranee
authors.initials: P
authors.lastname: Puranajoti
authors.affiliation: Chulabhorn Hospital, Bangkok 10210, Thailand.
authors.forename: Teerapat
authors.initials: T
authors.lastname: Ungtrakul
authors.affiliation: Chulabhorn Hospital, Bangkok 10210, Thailand.
authors.forename: Wanwisa
authors.initials: W
authors.lastname: Pongpun
authors.affiliation: Translational Research Unit, Chulabhorn Research Institute, Bangkok 10210, Thailand.
authors.forename: Saichit
authors.initials: S
authors.lastname: Thaeopattha
authors.affiliation: Translational Research Unit, Chulabhorn Research Institute, Bangkok 10210, Thailand.
authors.forename: Phanit
authors.initials: P
authors.lastname: Songvut
authors.affiliation: Laboratory of Pharmacology, Chulabhorn Research Institute, Bangkok 10210, Thailand; Environmental Toxicology Program, Chulabhorn Graduate Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, Office of Higher Education Commission, Ministry of Education, Bangkok 10400, Thailand. Electronic address: jutamaad@cri.or.th.
authors.forename: Jutamaad
authors.initials: J
authors.lastname: Satayavivad
mesh_terms: D000284:Administration, Oral; D000328:Adult; D035685:Andrographis / Q000737:chemistry*; D019540:Area Under Curve; D004224:Diterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D012995:Solubility; D013785:Thailand
chemical_list: D004224:Diterpenes
keywords: Andrographis paniculata; Andrographolide; Dissolution; Diterpenoids; Humans; Pharmacokinetics