Phase I metabolic reactions can occur during the absorptive phase, in the gut wall or liver, before the drug reaches the bloodstream. When this happens, the result is a reduction in the concentration of the drug before it reaches the circulation. In other words, there is a fraction of the drug that is lost before it is even absorbed. This is referred to as 'first-pass metabolism'. First-pass metabolism results when a compound (which may or may not have been altered by gut flora), enters the portal vein (which drains the GI system) and goes directly into the liver. The liver then removes substances quickly, preventing distribution to other parts of the body.
Morphine is an example of a drug that experiences a significant loss due to first-pass metabolism. After being swallowed, the drug is absorbed into the digestive system and enters the hepatic portal system. It is carried by the portal vein to the liver before it reaches the bloodstream. Cytochrome P-450 enzymes are found in high concentrations in the liver. Sometimes only a small amount of drug leaves the liver through the hepatic vein reaching the bloodstream. Eventually, the vasculature redistributes the drug back to the liver through the hepatic artery.
First-pass metabolism determines what fraction of an oral dose will reach the circulation - the bioavailable fraction. Intravenous drugs don’t experience this first-pass effect and are, by definition, 100% bioavailable. Drugs administered orally or inhaled, demonstrate less than 100% bioavailability. If a drug’s bioavailability is 20%, you would have to administer five times the dose orally than you would do intravenously to see the same effect (100/20 = 5). Examples of drugs exhibiting first-pass metabolism are aspirin and lidocaine. Some drugs, such as lidocaine, which have relatively low bioavailability are not given orally because of concerns about metabolite toxicity. Lidocaine would be completely metabolized by first-pass metabolism before it reached the bloodstream if it were given orally. Therefore, it is always administered IM or IV.
