title: Pharmacokinetics of clomipramine, an antidepressant, in poloxamer 407-induced hyperlipidaemic model rats.
abstract: OBJECTIVE
  This study was undertaken to investigate the effects of hyperlipidaemia on the pharmacokinetics of clomipramine, an antidepressant, particularly addressing the change of clomipramine distribution to plasma components in poloxamer 407-induced hyperlipidaemia model rats.
  
  
  METHODS
  Clomipramine pharmacokinetic studies in hyperlipidaemic rats were performed with clomipramine continuous infusion. Furthermore, clomipramine protein binding and distribution to the brain and plasma components such as lipoproteins were investigated.
  
  
  RESULTS
  Mean plasma concentration of clomipramine at steady state during continuous infusion (17.5µg/min/kg) in hyperlipidaemic rats (0.45±0.01µg/ml) was significantly higher than that in the control rats (0.30±0.02µg/ml). However, the amount of clomipramine in the brain in hyperlipidaemic rats (0.31±0.06µg/g) was dramatically lower than in the control rats (1.89±0.13µg/g). However, the plasma unbound fraction in hyperlipidaemic rats (0.98±0.05%) was significantly lower than that of the control rats (6.51±0.62%).
  
  
  CONCLUSIONS
  Lower distribution to the brain and lower plasma clearance of clomipramine in hyperlipidaemic rats resulted from lower plasma unbound fraction because of higher lipid-rich protein contents in blood. Results of this study provide useful information for dosage adjustment of clomipramine in hyperlipidaemia.
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kobuchi
authors.forename: Keizo
authors.initials: K
authors.lastname: Fukushima
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shibata
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ito
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Sugioka
authors.forename: Kanji
authors.initials: K
authors.lastname: Takada
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002997:Clomipramine / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D005070:Evans Blue / Q000378:metabolism; D006949:Hyperlipidemias / Q000139:chemically induced / Q000378:metabolism*; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D010949:Plasma / Q000378:metabolism; D020442:Poloxamer; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000928:Antidepressive Agents; D008074:Lipoproteins; D020442:Poloxamer; D005070:Evans Blue; D002997:Clomipramine