title: Development of 2-hydroxymethyl-3,5,6-trimethylpyrazine palmitate-loaded lipid emulsion: formulation, optimization, characterization, pharmacokinetics, biodistribution and pharmacodynamics.
abstract: BACKGROUND
  Tetramethylpyrazine (TMP) is used to treat cerebrovascular and cardiovascular diseases. However, it displays a short half-life that restricts clinical applications. 2-Hydroxymethyl-3,5,6-trimethylpyrazine (HTMP) is the principal active metabolite of TMP, with similar activity of TMP. Therefore, it makes sense to improve the biopharmaceutical characteristics via HTMP bypassing TMP.
  
  
  OBJECTIVE
  To prolong the half-life of HTMP and achieve improved bioavailability and efficacy compared to commercially available product of tetramethylpyrazine phosphate injection (TMPP-I).
  
  
  METHODS
  A lipophilic prodrug of HTMP, palmitate of HTMP (HTMPP) was synthesized, and then the lipid emulsion of HTMPP was developed. The middle cerebral artery occlusion (MCAO) model was applied to evaluate the efficacy in different administration group.
  
  
  CONCLUSIONS
  The optimized formulation consisted of 1.5% (w/v) HTMPP, 15% (w/v) soybean oil, 1.2% (w/v) soybean lecithin and 0.3% (w/v) poloxamer 188. The AUC0-180 min and the half-life of HTMP in HTMPP-LE was 2.05-fold and 1.48-fold greater than that in TMPP-I. The brain AUC0-120 min of HTMP in HTMPP-LE group increased by 145.6% compared to that in TMPP-I group. These differences could be primarily attributed to dissimilar metabolism between HTMPP and TMP. Consistently, HTMPP-LE exhibited better efficacy on ischemia/reperfusion model than TMPP-I.
  
  
  CONCLUSIONS
  The developed HTMPP-LE suggests a great therapeutic potential for clinical applications.
authors: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
authors: Ran
authors: R
authors: Cao
authors: Qian
authors: Q
authors: Li
authors: Hui
authors: H
authors: Li
authors: Ting
authors: T
authors: Chu
authors: Hui
authors: H
authors: Jin
authors: Sheng-Jun
authors: SJ
authors: Mao
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004655:Emulsions / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D008297:Male; D051379:Mice; D010168:Palmitates / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D011719:Pyrazines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: C115263:2-hydroxymethyl-3,5,6-trimethylpyrazine; D004655:Emulsions; D010168:Palmitates; D011719:Pyrazines