Role of gut contents, intestinal wall, and liver on the first pass metabolism and absolute bioavailability of isotretinoin in the dog.

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.