Liver: Introduction

Last updated: Sunday, July 12, 2015

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The liver is the main site of drug metabolism in the body, but not the only one. However, it is the principal location for cytochrome p450 metabolism. The liver’s main job in metabolism is to alter molecules so that they become more water soluble – this enables elimination by the kidney. Most drugs are pharmacologically inactivated by metabolism, but other drugs (pro-drugs such as cyclophosphamide) need to be metabolised to become active. Several drugs have pharmacological activity both before and after metabolism by the liver, due to the production of active metabolites. If you are interested, you can see the pathway by which paracetamol is metabolised in adults here - one of the metabolites is severely toxic to the liver if produced in sufficient quantity.

Courtesy of Simon Wills
The metabolic role of the liver is particularly important for drugs administered orally. Blood from the gut passes through the liver first before entering the systemic circulation, and this gives an opportunity for the organ to remove a high proportion of a dose. This first-pass metabolism’ significantly reduces the bioavailability of many oral drugs (e.g. opioids), and in some cases is so efficient that administration by the oral route is not possible (e.g. buprenorphine).

In addition to this major metabolic role, the liver does actually excrete some drugs from the body as well, via bile (e.g. rifampicin, leflunomide). Many of these drugs are excreted in the bile conjugated to bile salts. The flora of the bowel can digest these conjugates, releasing free drug into the gut, which then enables it to be re-absorbed. This is called entero-hepatic recycling and is an important mechanism by which blood levels of some drugs are maintained (e.g. oestrogens).

The liver also produces the majority of plasma proteins (e.g. albumin). These are important for transporting drug molecules around the body. The portion of a drug dose bound to plasma proteins cannot bind to receptors to exert a pharmacological effect and cannot be eliminated from the body. This is a major mechanism by which blood levels of highly plasma protein bound drugs are sustained.