Steady-state pharmacokinetics of isotretinoin and its 4-oxo metabolite: implications for fetal safety.
Isotretinoin is the most potent human teratogen on the market. Women for whom contraception fails may conceive during or soon after discontinuing isotretinoin therapy, making its elimination kinetics a crucial determinant of fetal safety. The steady-state pharmacokinetics of isotretinoin and its major 4-oxo metabolite were studied in 16 adult patients treated for acne who were receiving doses that ranged from 0.47 to 1.7 mg/kg daily. This is the first study of the pharmacokinetics of isotretinoin in women of childbearing age (n = 11). The clinical efficacy and tolerability of isotretinoin was investigated, and the correlation between these data and steady-state serum concentrations of isotretinoin was tested. The concentration-time data best fitted a two-compartment open model with linear elimination. There was no correlation between efficacy and tolerability of isotretinoin and steady-state serum concentrations. There was no correlation between dose of isotretinoin and steady-state concentration, due to the large variability in apparent clearance. Values for elimination half-life (t1/2) of isotretinoin and its metabolite were 29+/-40 hours and 22+/-10 hours, respectively. These data suggest a longer elimination t1/2 of the parent drug than previously reported. This is probably due to the longer sampling time used in this study (as long as 28 days). This study suggests that a greater variability exists in the safe time after discontinuation of the drug for onset of conception.
Nulman
I
I
Department of Pediatrics and Research Institute, The Hospital for Sick Children, Toronto, The University of Toronto, Ontario, Canada.
Berkovitch
M
M
Klein
J
J
Pastuszak
A
A
Lester
R S
RS
Shear
N
N
Koren
G
G
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000152:Acne Vulgaris / Q000188:drug therapy; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006207:Half-Life; D006801:Humans; D015474:Isotretinoin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007641:Keratolytic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D011247:Pregnancy; D013723:Teratogens / Q000493:pharmacokinetics*; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D007641:Keratolytic Agents; D013723:Teratogens; C002202:4-oxoretinoic acid; D014212:Tretinoin; D015474:Isotretinoin