The effect of the first liver passage
For a perorally administered pharmaceutical agent to exert its effects at the site of action, it usually must enter the systemic circulation. To do so, it must pass through the intestinal wall, the liver, and part of the circulatory system. Despite complete absorption in the intestine, the bioavailability of a drug – i.e. the portion that reaches the systemic circulation – can be reduced to a relevant extent by the first liver passage. This phenomenon is referred to as the hepatic first-pass effect. The reduction is caused by biotransformation of the active ingredients to metabolites and elimination into the bile. First-pass metabolism is often referred to the liver. However, some examples of drugs that are metabolized to a relevant extent already in the intestinal mucosa (in intestinal cells) have been documented, for example, ciclosporin, midazolam, nifedipine, and tacrolimus. High first-pass metabolism makes a drug susceptible to drug-drug interactions, adverse effects, and intra- and interindividual differences in efficacy. Oral administration may not be possible at all. Alternative dosage forms can be used to circumvent first-pass. These include, for example, suppositories, sublingual tablets, transdermal patches, nasal sprays, and injectables. An active ingredient does not necessarily have to be inactivated during biotransformation; it can also be metabolized to active metabolites. However, the first-pass effect is often referred to inactivation. Examples of agents with high first-pass metabolism include codeine, ciclosporin, desipramine, dextrometorphan, diclofenac, diltiazem, estradiol, lidocaine, losartan, midazolam, nifedipine, omeprazole, propranolol, terbinafine, and verapamil.
