title: Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease.
abstract: OBJECTIVE
  Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects.
  
  
  METHODS
  This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, AUC0-72 h and AUC0-∞ were calculated. Tolerance assessments were conducted throughout the study.
  
  
  RESULTS
  ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean tmax of huperzine A was 0.76-0.82 h; the AUC0-72 h and Cmax of huperzine A showed approximately dose-proportional increase over the dose range of 0.5-1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed.
  
  
  CONCLUSIONS
  ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers.
authors.affiliation: Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, China.
authors.forename: Jing-ying
authors.initials: JY
authors.lastname: Jia
authors.forename: Qian-hua
authors.initials: QH
authors.lastname: Zhao
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Yu-zhou
authors.initials: YZ
authors.lastname: Gui
authors.forename: Gang-yi
authors.initials: GY
authors.lastname: Liu
authors.forename: Da-yuan
authors.initials: DY
authors.lastname: Zhu
authors.forename: Chen
authors.initials: C
authors.lastname: Yu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Hong
mesh_terms: D000470:Alkaloids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D011355:Prodrugs; D012717:Sesquiterpenes; C508413:ZT-1 compound; C050426:huperzine A