Oral administration –> cross the gut mucosa –> enter portal circulation –> pass through the liver –> enter the systemic circulation.

Only un-ionised molecules can cross the mucosal barrier

Weakly acidic drugs (e.g. aspirin) begin to be absorbed in the acidic environment of the stomach

Weakly basic drugs only begin to be absorbed in the small intestine.

Drugs that are permanently ionised (e.g. the NDMR) are not absorbed from the gut at all.

Metabolism occurring in the liver is called ‘first-pass’ metabolism. The metabolism which happens in gut wall as in case of NTG is also first-pass metabolism. First-pass metabolism reduces the amount of drug that reaches its target site.

If liver is having a high metabolic capacity, in case of a particular drug, any drug entering the hepatocyte is quickly broken down. This maintains a concentration gradient favouring the dissociation of the drug from protein binding sites, and thus the overall hepatic metabolism is mainly related to hepatic blood flow. E.g. Propranolol

In case of drugs with lower hepatic metabolic capacity, drug remains bound to protein and so, the degree of protein binding influences entry to the hepatocyte than the hepatic blood flow

Sublingual and nasal routes have the advantage of rapid onset and bypassing of the portal circulation and hence the intake through these routes avoid first-pass metabolism.

Rectal route also avoids first-pass metabolism, but absorption is slow and can be incomplete.