Effect of route of administration and biliary excretion on the pharmacokinetics of isotretinoin in the dog.
Oral, intraportal, iv doses of isotretinoin were administered to dogs before and after bile duct cannulation to determine the effect of route of administration and biliary excretion on the pharmacokinetics of this compound. Blood and bile samples were collected and analyzed for isotretinoin using a gradient elution high performance liquid chromatographic method. Blood concentrations were decreased after bile duct cannulation. Decreases in the area under the blood concentration-time curves were greatest following oral dosing, intermediate following intraportal dosing, and least following iv dosing. These results indicate that biliary excretion impacts on the blood profile of isotretinoin as a function of route of administration and that the differences are the result of differences in first pass clearance. In addition, the apparent bioavailability of isotretinoin was 14% in bile cannulated dogs and 54% in the intact (uncannulated) animals, suggesting that enterohepatic recycling of isotretinoin may contribute to its oral bioavailability. Isotretinoin was excreted in the bile; predominantly as a conjugate. The largest percentage (approximately 27%) of the dose was excreted in the bile following intraportal infusion, an intermediate percentage (approximately 8.5%) after iv dosing, and the smallest percentage (approximately 3.3%) after oral dosing. When the amount of drug excreted in bile as intact drug and conjugate is divided by the area under the systemic blood concentration--time curve, the resulting apparent biliary clearances following oral and intraportal administration were almost identical whereas the apparent biliary clearance after iv dosing was substantially less.(ABSTRACT TRUNCATED AT 250 WORDS)
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001652:Bile Ducts; D002404:Catheterization; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005260:Female; D007275:Injections, Intravenous; D015474:Isotretinoin; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D011169:Portal Vein; D014212:Tretinoin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*
D014212:Tretinoin; D015474:Isotretinoin