title: Toxicokinetics and toxicity of potassium 2-(1-hydroxypentyl)-benzoate in beagle dogs.
abstract: Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB) is a prodrug of 3-n-butylphthalide (dl-NBP) for treatment of cerebral ischemic stroke in China, which undergoes lactonization to form dl-NBP in plasma. And, the phase II-III clinical trial of dl-PHPB has been approved by China Food and Drug Administration (CFDA) in 2013. In this study, a toxicity and toxicokinetics evaluation of dl-PHPB was performed using beagle dogs at specially high-dose 108 mg/kg/day (65-fold higher than humans at MHRD) for 4 weeks by intravenous administration, with a 3-week recovery period. And the plasma concentrations of dl-PHPB along with its metabolite dl-NBP were determined by HPLC-UV method. The results showed that dl-PHPB was quickly metabolized into dl-NBP, and no significant accumulation was observed. A slight to moderate behavior-associated toxicity was revealed in the process of delivery; and recovered to normal at the end of administration. Changes in the blood hematological profiles included significantly increased NEUT levels and lower LYM% content. Meanwhile, a notable increase in TG content was also observed in the serum biochemical parameters at 4-week post-exposure. These findings were reversible during the recovery period. The information from these studies would be taken into consideration for the interpretation of toxicology findings and provide a reference for clinical safety assessment.
authors.affiliation: a State Key Laboratory of Bioactive Substance and Function of Natural Medicines , Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 , China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.affiliation: a State Key Laboratory of Bioactive Substance and Function of Natural Medicines , Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 , China.
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Wang
authors.affiliation: b New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences , Beijing 100050 , China.
authors.forename: Ai-Ping
authors.initials: AP
authors.lastname: Wang
authors.affiliation: a State Key Laboratory of Bioactive Substance and Function of Natural Medicines , Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 , China.
authors.forename: Shao-Feng
authors.initials: SF
authors.lastname: Xu
authors.affiliation: b New Drug Safety Evaluation Center, Institute of Materia Medica, Chinese Academy of Medical Sciences , Beijing 100050 , China.
authors.forename: Hong-Tao
authors.initials: HT
authors.lastname: Jin
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology; D002681:China; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D015394:Molecular Structure; D010420:Pentanes / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology*; D066007:Toxicokinetics
chemical_list: C511222:2-(1-hydroxypentyl)-benzoate; D001565:Benzoates; D001572:Benzofurans; D010420:Pentanes; C027125:3-n-butylphthalide; D011188:Potassium
keywords: 3-n-butylphthalide; Toxicokinetics; potassium 2-(1-hydroxypentyl)-benzoate; toxicity