Role of gut contents, intestinal wall, and liver on the first pass metabolism and absolute bioavailability of isotretinoin in the dog
Cotler, S.; Buggé, C.J.; Colburn, W.A.
Drug Metabolism and Disposition the Biological Fate of Chemicals 11(5): 458-462
1983
ISSN/ISBN: 0090-9556 PMID: 6138231 Document Number: 215330
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.