title: A physiologically based pharmacokinetic model for retinoic acid and its metabolites.
abstract: BACKGROUND
  A physiologically based pharmacokinetic (PBPK) model for all-trans-retinoic acid (tretinoin) was developed to provide a coherent description of tretinoin absorption, distribution metabolism, and excretion across species and routes of administration.
  
  
  OBJECTIVE
  The goal of developing such a model is to provide a measure of internal dose that would be a biologically relevant surrogate for administered dose in assessing human teratogenic risk from topically applied tretinoin emollient cream.
  
  
  METHODS
  The developed PBPK model included compartments for plasma, liver, gut, intestinal lumen, fat, skin, richly and slowly perfused tissues, placenta, and embryo. Tretinoin metabolism to 13-cis retinoic acid, oxidation, and glucuronidation were incorporated. Dose surrogates, including the maximum plasma concentration (Cmax) and area under the concentration-versus-time curve were calculated from the model.
  
  
  RESULTS
  The ability of the model to predict tretinoin pharmacokinetics and to extrapolate across species and routes of administration was tested and validated. Model-derived estimates of dose surrogates demonstrated that the internal exposure to retinoids after topical treatment with 0.05% tretinoin emollient cream is minimal in comparison to that for teratogenic oral doses. The ratio of areas under the curve for total active retinoids after teratogenic oral doses in monkeys versus therapeutic topical doses in human beings, for example, was greater than 450,000 to 1.
  
  
  CONCLUSIONS
  For topical application of tretinoin in human beings, detoxification via the glucuronidation pathway predominates, resulting in a much lower internal exposure to active retinoids than was inferred from total radioactivity data. The model predicts that topical application of tretinoin results in an internal exposure that is four to six orders of magnitude lower than a minimally teratogenic dose.
authors.affiliation: K.S. Crump Division, ICF Kaiser International, Ruston, LA 71270, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Clewell
authors.forename: M E
authors.initials: ME
authors.lastname: Andersen
authors.forename: R J
authors.initials: RJ
authors.lastname: Wills
authors.forename: L
authors.initials: L
authors.lastname: Latriano
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007641:Keratolytic Agents / Q000493:pharmacokinetics*; D008954:Models, Biological; D014212:Tretinoin / Q000493:pharmacokinetics*
chemical_list: D007641:Keratolytic Agents; D014212:Tretinoin