Chronopharmacokinetics of imipramine and desipramine in rat forebrain and plasma after single and chronic treatment with imipramine.
Daily variations in the pharmacokinetics of imipramine (IMI) could contribute to circadian phase-dependent effects of the drug. Therefore, the chronopharmacokinetics of IMI and its metabolite, desipramine (DMI), were studied after single and chronic application. Male rats were synchronized to a 12:12 hour light:dark (L:D) regimen with lights on from 07:00 to 19:00 (dark, 19:00-07:00). In single-dose experiments rats were injected with IMI (10 mg/kg) i.p. or i.v. at 07:30 or 19:30 and groups of rats were killed 0-22 hours thereafter. After chronic application of IMI in drinking water (approximately 15 mg/kg/d) groups of rats were killed during the 14th day of treatment at 02:00, 08:00, 14:00, and 20:00, respectively. Brain and plasma concentrations of IMI and DMI were determined by reversed-phase high-performance liquid chromatography with ultraviolet detection. After single i.p. application of IMI, maximal brain concentrations (Cmax) of IMI and DMI were nearly twofold higher in darkness (IMI, 4.8 micrograms/g; DMI, 1.8 micrograms/g) than in light (IMI, 2.85 micrograms/g; DMI, 0.85 microgram/g). Also, the area under the curve (AUC) (0-22 hours) was about 1.6-fold greater in darkness than in light for IMI and DMI; half-lives were not circadian phase dependent. After i.v. injection of IMI, the AUC in brain was also about 30% greater in darkness than in light. After chronic application of IMI in drinking water, brain concentrations of IMI and DMI varied more than threefold within 24 hours. The data demonstrate that the pharmacokinetics of IMI and DMI are circadian phase dependent. It is assumed that circadian variations in drug distribution are more likely to contribute to the drug's chronopharmacokinetics than variations in the drug's metabolism. The 24-hour variations in the drug's concentrations after chronic IMI application in drinking water can be explained by the drinking behavior of the rats, which by itself is altered by IMI.
Lemmer
B
B
Zentrum der Pharmakologie, J. W. Goethe-Universität, Frankfurt, Germany.
Holle
L
L
D000704:Analysis of Variance; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002940:Circadian Rhythm; D003891:Desipramine / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D007099:Imipramine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008027:Light; D008297:Male; D016548:Prosencephalon / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D007099:Imipramine; D003891:Desipramine