title: Pharmacokinetics of tolbutamide and its metabolite 4-hydroxy tolbutamide in poloxamer 407-induced hyperlipidemic rats.
abstract: Under hyperlipidemic conditions, there are likely to be alterations in the pharmacokinetics of CYP2C11 substrates following decreased expression of CYP2C11, which is homologous to human CYP2C9. The pharmacokinetics of tolbutamide (TB) and its metabolite 4-hydroxy tolbutamide (4-OHTB) were evaluated as a CYP2C11 probe after intravenous and oral administration of 10 mg/kg tolbutamide to poloxamer 407-induced hyperlipidemic rats (HL rats). Changes in the expression and metabolic activity of hepatic CYP2C11 and the plasma protein binding of tolbutamide in HL rats were also evaluated. The total area under the plasma concentration-time curve (AUC) of tolbutamide in HL rats after intravenous administration was comparable to that in controls due to their comparable non-renal clearance (CLNR ). The free fractions of tolbutamide in plasma were comparable between the control and HL rats. The 4-hydroxylated metabolite formation ratio (AUC4-OHTB /AUCTB ) in HL rats was significantly smaller than that in the control rats as a result of the reduced expression of hepatic CYP2C11 (by 15.0%) and decreased hepatic CLint (by 28.8%) for metabolism of tolbutamide to 4-OHTB via CYP2C11. Similar pharmacokinetic changes were observed in HL rats after oral administration of tolbutamide. These findings have potential therapeutic implications, assuming that the HL rat model qualitatively reflects similar changes in patients with hyperlipidemia. Since other sulfonylureas in clinical use are substrates of CYP2C9, their hepatic CLint changes have the potential to cause clinically relevant pharmacokinetic changes in a hyperlipidemic state.
authors.affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea.
authors.forename: Mi Ran
authors.initials: MR
authors.lastname: Choi
authors.forename: Mi Hye
authors.initials: MH
authors.lastname: Kwon
authors.forename: Yong Yeon
authors.initials: YY
authors.lastname: Cho
authors.forename: Hye Duck
authors.initials: HD
authors.lastname: Choi
authors.forename: Yu Chul
authors.initials: YC
authors.lastname: Kim
authors.forename: Hee Eun
authors.initials: HE
authors.lastname: Kang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004195:Disease Models, Animal; D006900:Hydroxylation; D006949:Hyperlipidemias / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D020442:Poloxamer / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism*; D014044:Tolbutamide / Q000493:pharmacokinetics*
chemical_list: D007004:Hypoglycemic Agents; D020442:Poloxamer; D014044:Tolbutamide; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase
keywords: 4-hydroxy tolbutamide; CYP2C11; hyperlipidemia; pharmacokinetics; plasma protein binding; tolbutamide