Adipose tissue distribution and chemical structure of basic lipophilic drugs: desipramine, N-acetyl desipramine, and haloperidol.
Single-dose intravenous injections of desipramine to rats resulted in a distribution pattern typical of basic lipophilic drugs, i.e., highest concentrations in lung and lowest in adipose tissue and plasma. In contrast, after N-acetyldesipramine, a non-basic analogue of desipramine with comparable lipophilicity, concentrations of this drug in adipose tissue were much higher than in lean tissue or plasma as a result of redistribution into the former and rapid disappearance from the latter tissue. N-Acetyldesipramine had much lower plasma and tissue half-lives than desipramine, but at the same time a much higher adipose/plasma concentration ratio and adipose storage index. Chronic administration of the basic lipophilic drug, haloperidol, to rats in their diet over 21 days resulted in a steady-state distribution pattern with highest concentrations in lung and lowest concentrations without accumulation in adipose tissue. This study provides additional evidence for the influence of basic groups on the distribution of lipophilic drugs. Thus, basic lipophilic drugs do not undergo redistribution into adipose tissues, possibly because of a competition by stronger binding to lean tissue as a result of lysosomotropism.
Moor
M J
MJ
Department of Pharmacology, University of Bern, Switzerland.
Steiner
S H
SH
Jachertz
G
G
Bickel
M H
MH
D000273:Adipose Tissue / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D003891:Desipramine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006220:Haloperidol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
C076162:N-acetyldesipramine; D006220:Haloperidol; D003891:Desipramine