First-pass elimination takes place when a drug is metabolised between its site of administration and the site of sampling for measurement of drug concentration. Clinically, first-pass metabolism is important when the fraction of the dose administered that escapes metabolism is small and variable. This is why you see 3000 times the amount of of a vitamin in oral supplements, because manufacturers know by the time their product reaches its target tissue, there is hardly anything left!
The liver is usually assumed to be the major site of first-pass metabolism of a drug administered orally, but other potential sites are the gastrointestinal tract, blood, vascular endothelium, lungs and the arm from which venous samples are taken.
Bioavailability, defined as the ratio of the areas under the blood concentration-time curves, after extra- and intravascular drug administration (corrected for dosage if necessary), is often used as a measure of the extent of first-pass metabolism. When several sites of first-pass metabolism are in series, the bioavailability is the product of the fractions of drug entering the tissue that escape loss at each site. The extent of first-pass metabolism in the liver and intestinal wall depends on a number of physiological factors. The major factors are enzyme activity, plasma protein and blood cell binding and gastrointestinal motility.
One major therapeutic implication of extensive first-pass metabolism is that much larger oral doses than intravenous doses are required to achieve equivalent plasma concentrations. For some drugs, extensive first-pass metabolism precludes their use as oral agents (e. g. lignocaine, naloxone and glyceryl trinitrate).
First-pass elimination makes pills and powders virtually useless without the use of extremely high – unsafe doses of vitamins and minerals.