First-pass metabolism

First-pass metabolism is the breakdown of a swallowed substance by the gut wall and liver before it reaches the general bloodstream, reducing the amount that becomes active.

After a compound is absorbed from the intestine, the blood carrying it flows through the portal vein directly to the liver. Liver enzymes, particularly the cytochrome P450 family, metabolize a portion of the compound during this passage, and intestinal enzymes may act on it even earlier. What remains then enters general circulation. Routes that avoid the portal system, such as sublingual, buccal, inhaled, transdermal, and rectal administration, bypass much of this effect.

First-pass metabolism is a major reason oral cannabidiol has low and variable bioavailability. It also produces metabolites, including 7-hydroxy-cannabidiol, that circulate alongside the parent compound. Fatty meals appear to reduce the first-pass loss for CBD by changing how it is absorbed, which is why studies report higher exposure when it is taken with food. Readers meet the concept in explanations of why the same milligram amount can behave differently depending on how it is taken.