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Drugs are introduced to the body through a variety of routes including oral, intramuscular, intravenous, subcutaneous, sublingual, rectal and so on. Among them around 60% drugs are administrated orally as liquids, capsules, tablets, or chewable tablets. Oral drugs are,

Noninvasive

Patient compliant

Easy to use

Don't require sterile conditions.

After administration and disintegration in the stomach, the small intestine absorbs the majority of oral medications. The medicine passes through the intestinal wall and into the liver before being delivered to its target site via the bloodstream.

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The intestine acts as a gateway to the liver and is essential for drug absorption and first-pass removal. The superior mesenteric artery delivers blood to the small intestine, while the hepatic portal vein flow is made up of venous returns from the spleen, pancreas, gallbladder, and gastrointestinal tract, including the stomach. Simple columnar epithelial cells known as enterocytes line the inner walls of the small intestine and are endowed with absorptive transmembrane transporters. The villi and microvilli, which are many protrusions on these cells, increase the surface area multiple-fold to absorb drug molecules or nutrients from the gut lumen. Drug absorption in the intestine is mostly regulated by physicochemical conditions in the lumen through the epithelial barrier that is mostly accomplished by diffusion, with carrier-mediated transport.

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The hepatic portal vein is a vessel which moves blood from the spleen and gastrointestinal tract to the liver. After the oral administration, drugs pass through the small intestine and enter to the portal vein or intestinal lymphatic system. Soluble and small drugs are preferentially transported by the portal vein. These drugs can immediately accumulate in the liver and are then metabolized by enzymes, which can lower the drug concentration in the bloodstream.

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The liver metabolizes many drugs, sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system.
This first pass through the liver thus may greatly reduce the bioavailability of the drug.
The process of metabolism is divided into 3 phases.

Phase I metabolism involves functionalization reactions. Phase II drug metabolism is a conjugation reaction.

Phase III refers to transporter-mediated elimination of drug and metabolites from the body normally via liver, gut, kidney, or lung.

Once in the liver, enzymes convert pro-drugs to active metabolites or convert active drugs to inactive forms. The liver’s primary mechanism for metabolizing drugs is via a specific group of cytochrome P-450 enzymes. The level of these cytochrome P-450 enzymes controls the rate at which many drugs are metabolized. Many substances (such as drugs and foods) affect the cytochrome P-450 enzymes; which eventually affect the drug's action by altering enzyme's ability to break down a drug.

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Impact of first-pass metabolism on drugs

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Impact of first-pass metabolism on drugs

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Drug enters the liver hepatocytes, specifically in the smooth endoplasmic reticular for metabolism. First pass metabolism directly effects on the bioavailability of a drug. Generally a certain amount of drug is ingested with the tablet by oral administration. Then, the drug absorbed in intestine and via portal vein the absorbed drug is reached in the liver. In liver, the metabolism starts. Particular changes happen in this metabolism process which has direct impact on drug bioavailability. Such of them are as below:

Active drugs become inactive by getting metabolized and it happens in the most of the cases.

If we take a drug and those are not mutually exclusive but that drug could be toxic or our body could view that drug as being toxic, then after first pass metabolism it becomes non-toxic.

Inactive drugs could be active after the first pass metabolism. These drugs are called as “pro-drug”. For example, pro-drug codeine become active morphine after first pass metabolism by the hepatic enzymes.

In some cases, non-toxic drugs can be converted to toxic drug after the metabolism. For example, 95% cases acetaminophen stays non-toxic but in some cases it converted to toxic state.

After metabolism lipid-soluble drugs become more water soluble.

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Relation of first-pass effect to bioavailability

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Relation of first-pass effect to bioavailability

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First pass metabolism or first pass clearance has a significant relationship with hepatic extraction ratio. Hepatic extraction ratio is the fraction of the drug entering the liver in the blood which is then removed irreversibly during blood passes through the liver. So, we can say if any drug has low hepatic extraction ratio, it will also have low first pass clearance.
There is a considerable difference in the effect of hepatic enzyme inhibition and activation on the bioavailability of drugs with high and low extraction ratios.

For drugs with high hepatic extraction ratio, a small change in liver enzyme activity will lead to only a small change in first pass metabolism, but a large clinically significant change in bioavailability

For drugs with low hepatic extraction ratio, a change in liver enzyme activity will lead to a proportional change in first pass metabolism, which may not change the bioavailability by a clinically significant degree.