Appropriate dosing regimens for treating juvenile rats with desipramine for neuropharmacological and behavioral studies.
The tricyclic antidepressants, including desipramine (DMI), are no better than placebo in treating childhood and adolescent depression, but are effective in adult depression. Animal studies comparing the effects of DMI in juveniles and adults are complicated by age-related variations in elimination rates. Thus, different dosing regiments are needed to achieve similar brain drug levels in juvenile and adult rats. We compared the half-life of DMI as well as the brain and serum concentrations of DMI and its active metabolite desmethyldesipramine in juvenile and adult rats after various drug administration paradigms. After acute i.p. administration DMI is eliminated from the brain more slowly in postnatal day (PND) 21 and 28 rats as compared to adults. After chronic i.p. administration (for 4-5 days between PND 9 and 28), lower doses of DMI are needed with juvenile rats to obtain the same brain DMI concentrations as adults. By contrast, 2 weeks of continuous drug delivery (minipump) to PND 21-35 and adult rats result in similar brain DMI concentrations. Thus, the pharmacokinetic properties of DMI varies with the age of the animal and dosing of DMI and needs to be carefully adjusted in order to have appropriate brain levels of the drug.
Kozisek
Megan E
ME
Department of Pharmacology and Experimental Neuroscience, 985800 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA. mlavicky@unmc.edu
Deupree
Jean D
JD
Burke
William J
WJ
Bylund
David B
DB
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism / Q000493:pharmacokinetics*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003891:Desipramine / Q000378:metabolism / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006207:Half-Life; D007099:Imipramine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013550:Swimming; D013997:Time Factors
D000929:Antidepressive Agents, Tricyclic; C036691:didesipramine; D007099:Imipramine; D003891:Desipramine