Abstract
The pharmacokinetic profiles of imipramine (IMI) and its major active metabolites were determined in pregnant rats following an acute 30 mg/kg ip IMI dose. At timed intervals from 10 min to 18 hr, groups of five animals were sacrificed and whole blood, plasma, maternal and fetal brain, fetal liver, placental tissue, and whole fetus were retained for measurements of drug concentrations. IMI, 2-hydroxyimipramine (2-OH-IMI), and desipramine (DMI) rapidly appeared in all tissues and showed complex disposition kinetics. The 2-hydroxydesipramine (2-OH-DMI) metabolite was detectable in occasional samples. The area under the drug concentration-time curve for both IMI and DMI was more than 7-fold greater in whole fetus than in maternal plasma. Drug concentrations were greater in fetal brain than in whole fetus. The DMI concentration exceeded that of IMI in all tissues and DMI persisted in tissues longer: mean residence time for DMI in whole fetus was 21.2 hr compared to 3.5 hr for IMI. The area under the curve of DMI in fetal brain was 5.35 times greater than that of IMI. These results demonstrate that IMI and two of its major metabolites freely distribute to the rat fetus, that drug distribution within the fetus is regional, and that the major drug to which the fetal brain is exposed following maternally administered IMI is DMI. Studies of the teratogenic effects of extensively biotransformed drugs like IMI should consider the effects of active metabolites.