title: Role of gut contents, intestinal wall, and liver on the first pass metabolism and absolute bioavailability of isotretinoin in the dog.
abstract: The absolute bioavailability and first pass metabolism of isotretinoin by the gut contents, gut wall, and liver of the dog were assessed with a sensitive and specific high performance liquid chromatographic analytical method and a recently published pharmacokinetic model. [12C]- and [14C]isotretinoin were simultaneously administered to the dog by iv and oral routes, respectively. Blood samples were obtained from the jugular and the portal veins at specified times to quantify [12C]isotretinoin and [14C]isotretinoin blood concentrations. In addition, blood, bile, urine, and the gastrointestinal contents were analyzed for carbon-14-containing materials. The harmonic mean elimination half-life (t 1/2 beta) for the simultaneous iv and oral administration was approximately 5.5 hr. The mean +/- SD blood clearance (ClB) following iv administration and the intrinsic clearance following oral administration were 5.19 +/- 2.40 and 6.63 +/- 3.72 ml/min/kg, respectively. The average absolute bioavailability was 21%, indicating an overall first pass effect of approximately 80%. The majority (approximately 72%) of the first pass effect occurred in the gut lumen with the gut wall and liver making a lesser contribution to the overall first pass effect. These results demonstrated that the low absolute bioavailability was largely due to loss of drug prior to reaching the portal circulation; and analysis of gut contents for total carbon-14 activity suggested that a fraction of isotretinoin dose was biologically or chemically degraded in the gut lumen prior to absorption.
mesh_terms: D000818:Animals; D001682:Biological Availability; D004064:Digestive System / Q000378:metabolism*; D004285:Dogs; D007413:Intestinal Mucosa / Q000378:metabolism*; D015474:Isotretinoin; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D014212:Tretinoin; D015474:Isotretinoin