Influence of pregnancy on the pharmacokinetic disposition of two aromatic retinoids (etretinate and acitretin) in the rat. II. Single and multiple oral dosing studies.
During a multiple dose regimen of etretinate, steady state trough plasma concentrations of etretinate in nonpregnant female rats reached their peak levels (15 ng/ml) by day 10 and remained between 10 and 15 ng/ml through day 19. Steady state trough concentrations of acitretin in nonpregnant animals following etretinate multiple dosing reached their peak levels (53 ng/ml) at day 7 and declined to 16 ng/ml at day 19. A similar decline was observed following multiple oral dosing of acitretin itself, suggesting autoinduction of acitretin clearance. In single dose studies, the apparent oral bioavailability of etretinate was similar (4-5%) for both pregnant and nonpregnant rats (p greater than 0.05). The ratio of the AUC of acitretin to etretinate following etretinate administration was 10-fold greater than that reported for iv studies. Acitretin bioavailability was 10-fold greater than that for etretinate (57%); again, there was no difference between the pregnant and nonpregnant groups (p greater than 0.05). The apparent mean residence time and t1/2 of both etretinate and acitretin were similar for both groups (pregnant and nonpregnant). However, the time course of both etretinate and acitretin was greatly prolonged compared to iv studies. These studies suggest that the marked differences in the bioavailability (etretinate vs. acitretin) and in the time course of these retinoids (iv vs. oral) could have a substantial impact on their apparent toxicity.
Brouwer
K R
KR
College of Pharmacy, University of Kentucky, Lexington 40536.
McNamara
P J
PJ
D017255:Acitretin; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D005050:Etretinate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014212:Tretinoin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D014212:Tretinoin; D005050:Etretinate; D017255:Acitretin