Gastric Emptying
The rate of gastric emptying determines the rate at which a drug is delivered to the small intestine, which is the major site of absorption. A delay between dose administration and the detection of the drug in the circulation is seen frequently after oral dosing, and is usually caused by delayed gastric emptying. The co-administration of drugs that slow gastric emptying, for example antimuscarinics, can alter the rate of drug absorption.
Food has a complex effect on drug absorption since it reduces the rate of gastric emptying and delays absorption, but it can also alter the total amount of drug absorbed.
First-pass metabolism
Metabolism of drugs can occur prior to and during absorption, and this can limit the amount of parent compound reaching the general circulation. Drugs taken orally have to pass four major metabolic barriers before they reach the general circulation.
Intestinal lumen: This contains digestive enzymes secreted by the mucosal cells and pancreas that are able to split amide, ester and glycosidic bonds. Intestinal proteases prevent the oral administration of peptides, which are the usual products derived from molecular biological approaches to drug development. In addition, the lower bowel contains large numbers of aerobic and anaerobic bacteria, which are capable of performing a range of metabolic reactions, especially hydrolysis and reduction.
Intestinal wall: The cells of the wall are rich in enzymes such as monoamine oxidase (MAO), L-aromatic amino acid decarboxylase, CYP3A4 and the enzymes responsible for the phase 2 conjugation reactions. In addition, the luminal membrane of the intestinal cells contains the efflux transporter PGP, which transfers some drugs that have entered the cell back into the intestinal lumen. Drug molecules that enter the enterocyte may undergo three possible fates – i.e. diffuse into the hepatic portal circulation, undergo metabolism within the cell, or be transported back into the gut lumen by PGP. There are overlapping substrate specificities of CYP3A4 and PGP, and for common substrates the combined actions can prevent the majority of an oral dose reaching the portal circulation.
Liver: Blood from the intestine is delivered directly to the liver, which is the major site of drug metabolism in the body.
Lung: Cells of the lung have high affinity for many basic drugs and are the main site of metabolism for many local hormones via MAO or peptidase activity.
