Steady-state pharmacokinetics of isotretinoin and its 4-oxo metabolite: implications for fetal safety

J Clin Pharmacol. 1998 Oct;38(10):926-30. doi: 10.1002/j.1552-4604.1998.tb04388.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Drug-Induced / etiology
  • Acne Vulgaris / drug therapy
  • Adolescent
  • Adult
  • Area Under Curve
  • Chromatography, High Pressure Liquid
  • Female
  • Half-Life
  • Humans
  • Isotretinoin / pharmacokinetics*
  • Isotretinoin / therapeutic use
  • Keratolytic Agents / pharmacokinetics*
  • Keratolytic Agents / therapeutic use
  • Male
  • Pregnancy
  • Teratogens / pharmacokinetics*
  • Tretinoin / analogs & derivatives*
  • Tretinoin / pharmacokinetics


  • Keratolytic Agents
  • Teratogens
  • 4-oxoretinoic acid
  • Tretinoin
  • Isotretinoin