title: Steady-state pharmacokinetics of isotretinoin and its 4-oxo metabolite: implications for fetal safety.
abstract: 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.
authors.affiliation: Department of Pediatrics and Research Institute, The Hospital for Sick Children, Toronto, The University of Toronto, Ontario, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Nulman
authors.forename: M
authors.initials: M
authors.lastname: Berkovitch
authors.forename: J
authors.initials: J
authors.lastname: Klein
authors.forename: A
authors.initials: A
authors.lastname: Pastuszak
authors.forename: R S
authors.initials: RS
authors.lastname: Lester
authors.forename: N
authors.initials: N
authors.lastname: Shear
authors.forename: G
authors.initials: G
authors.lastname: Koren
mesh_terms: 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
chemical_list: D007641:Keratolytic Agents; D013723:Teratogens; C002202:4-oxoretinoic acid; D014212:Tretinoin; D015474:Isotretinoin