title: Mild hypothermia decreases the total clearance of glibenclamide after low dose administration in rats.
abstract: OBJECTIVE
  Low dose glibenclamide exhibits pleiotropic protective effects in different central nervous system diseases. Previously, we have shown that mild hypothermia enhanced the efficacy of glibenclamide in the cultured cortical neuronal cells. This study aims to evaluate the impact of mild hypothermia on the pharmacokinetics of low dose glibenclamide in rats via its cytochrome P450 2C9 (CYP2C9) metabolic pathway.
  
  
  METHODS
  Male Sprague-Dawley rats were maintained at 37°C (normothermic group) or cooled to 33°C (hypothermic group). Glibenclamide (33μg/kg) or diclofenac (10mg/kg, a probe drug for assessing the activity of CYP2C9 which involves in glibenclamide and diclofenac metabolism in liver) were intravenously administered at 10min after stabilization of temperature. Plasma samples were collected at 9 different time points. Glibenclamide and diclofenac in sera were separated by liquid chromatography and quantified with tandem mass spectrometry.
  
  
  RESULTS
  Compared with normothermia, mild hypothermia significantly decreased the total clearance of glibenclamide (16.00±4.1-6.72±2.1mL/min/kg; p<0.01), and there was a non-significant trend in a slightly higher half-life, (1.64±0.34-2.71±1.7h, p=0.157). Area under the plasma concentration versus time curve (AUClast) in the hypothermic group was increased (33.2±11-77.8±18hng/mL, p<0.01). Moreover, mild hypothermia reduced the total clearance of diclofenac (10.33±1.53-7.20±1.66mL/min/kg, p<0.01), indicating that the CYP2C9 activity was compromised in reduced temperature.
  
  
  CONCLUSIONS
  Mild hypothermia reduced the total clearance of glibenclamide, probably via mediating the activity of CYP2C9. The impact of hypothermia in clinical application of glibenclamide should be considered.
authors.affiliation: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ji
authors.affiliation: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yafang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Kaibin
authors.initials: K
authors.lastname: Huang
authors.affiliation: Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: pansuyue82@126.com.
authors.forename: Suyue
authors.initials: S
authors.lastname: Pan
mesh_terms: D000818:Animals; D001831:Body Temperature; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism*; D004008:Diclofenac / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000493:pharmacokinetics*; D007036:Hypothermia, Induced; D008297:Male; D018696:Neuroprotective Agents / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley
chemical_list: D018696:Neuroprotective Agents; D004008:Diclofenac; D065729:Cytochrome P-450 CYP2C9; D005905:Glyburide
keywords: CYP2C9; Glibenclamide; Mild hypothermia; Pharmacokinetics