title: Chronopharmacological assessment identified GLUT4 as a factor responsible for the circadian variation of the hypoglycemic effect of tolbutamide in rats.
abstract: The circadian relationship between the pharmacokinetics and pharmacodynamics of tolbutamide in rats was analyzed using a compartment model. The basal concentration of plasma glucose had a circadian rhythm with the acrophase at 15:19 h. After intravenous administration of tolbutamide at 06:00, 14:00, or 18:00 h, the hypoglycemic effect showed a circadian variation, with the greatest effect at 18:00 h and the lowest effect at 06:00 h. The time courses of unbound tolbutamide concentration in plasma after intravenous administration were predicted using the model-estimated total concentration of tolbutamide and the albumin concentration and resulted in profiles that did not vary with the time of administration. Significant low insulin resistance was observed at 18:00 h to i.v. glucose and insulin loads. There was no obvious time dependency in the expression of glucose transporter 4 (GLUT4) in epididymal adipocytes. The hypoglycemic rate estimated from the plasma glucose concentration was described by the conventional pharmacokinetic-pharmacodynamic model with an effect compartment. The time courses of theoretical signals in the effect compartment described the observed circadian changes in the increased expression profile of GLUT4 normalized by the increased plasma insulin (IRI) concentration (ΔGLUT4/ΔIRI) after dosing. Thus, the time dependency in glucose uptake is responsible for the circadian variation of the hypoglycemic effect of tolbutamide.
authors.affiliation: Division of Pharmaceutics, Osaka University of Pharmaceutical Sciences, Japan. miyazaki@gly.oups.ac.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Toshiki
authors.initials: T
authors.lastname: Fujii
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Takeda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Magotani
authors.forename: Kazunori
authors.initials: K
authors.lastname: Iwanaga
authors.forename: Masawo
authors.initials: M
authors.lastname: Kakemi
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002909:Chronobiology Phenomena; D002940:Circadian Rhythm / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D014044:Tolbutamide / Q000097:blood / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; C495694:Slc2a4 protein, rat; D014044:Tolbutamide; D005947:Glucose