Lymphatic drug absorption

The entire dose of most orally-administered drugs must negotiate both the barrier of the intestinal wall to reach the hepatic circulation, and then the potential for hepatic metabolism as the drug passes through the liver, before reaching the systemic circulation. However, a few drugs – particularly drugs with extremely high lipid solubility, and thus which would be predicted to have extremely low oral bioavailability – are able to bypass the liver to some extent and thus enter the systemic circulation without being exposed to hepatic first-pass metabolism. As a result, oral bioavailability can be higher, sometimes much higher, than might have been predicted based on knowledge of the drug’s hepatic extraction ratio.

After diffusion into enterocytes of the intestinal wall, association of the drug with dietary fat is followed by transport (likely mediated by chylomicrons) into lymphatic vessels draining the walls of the intestine. The fluid in these vessels drains via the thoracic duct into the systemic circulation, at the junction of the left subclavian vein and the left internal jugular vein in the upper thorax.

For a drug with a hepatic extraction ratio of 0.9 and thus an oral bioavailability of 10% (assuming the fraction of drug absorbed from the gut is 1), absorption of just 25% of the administered dose via the lymphatic system would increase oral bioavailability by more than 3-fold.