Metabolism

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Chapter 17 Metabolism

Chapter contents

The liver 129

The gastrointestinal tract 130

Enterohepatic cycle or circulation 131

The Liver

• One of the most metabolically active areas in the body.

• The main site of detoxification in the body.

• The detoxification process has two phases: phase I (involves an enzyme complex called cytochrome p450) and phase II.

• This processing, which allows chemicals to be made water soluble and excreted from the body, can make it difficult to achieve a sufficient concentration of remedy in the body.

• Liver disease causes great problems because harmful substances are not prepared for removal from the body.

The First-Pass Mechanism

All orally administered remedies (apart from the very small amounts absorbed through the mucous membranes in the mouth) pass through the liver before they reach the tissues. Some drugs (such as nitroglycerin) are almost completely removed by the liver at the first pass (i.e. on the first go). Others take a little longer because they are not completely removed by this system (due to the enterohepatic cycle or they are just more difficult to remove). Other drugs rely on this system to activate their components, as the liver will change the chemistry of the drug.

The more resistant a drug is to the first-pass mechanism, the longer its half-life (i.e. the time it takes for a remedy to halve its dosage in the body). It is difficult to say how herbal remedies are affected by the first-pass mechanism because the constituents and their interactions are so complex. However, some elements of the first-pass mechanism will be involved in the metabolism of herbal remedies.

Liver Enzyme Induction and Inhibition

Enzymes can be encouraged to speed up or slow down. For example, cytochrome p450 (the enzyme involved in phase I in the liver), of which there are several variations, can be particularly affected.

• Enzyme Induction

Many substances already present in the body, or that can be introduced (e.g. nicotine, caffeine, alcohol, dioxin, oranges, tangerines and excess protein from high-protein diets) will speed up the metabolism. Chemicals such as hormones will also increase the activity of enzymes.

Hypericum (St John’s wort) increases the rate of action of cytochrome p450.

• Enzyme Inhibition

Certain flavonoids and furanocoumarins (see Chapter 21 ‘Phenols’, p. 156) inhibit cytochrome p450. Naringenin (found in grapefruits) is a well-known flavonoid that inhibits cytochrome p450; bergapten and quercitin also have this effect. Such inhibition can be a greater problem than enzyme induction, as an unusual rise of a drug or remedy in the system beyond its therapeutic limit can be harmful to the body.

Note: water-soluble chemicals tend to be less toxic than lipid-soluble chemicals because they can be so easily removed via the kidneys. Lipid-soluble compounds, if not dealt with by the detoxification pathways in the liver, tend to be stored in fatty tissues and released at a time when fat stores are utilized, for example if the patient fasts. This is why fasting can make patients ill.

The Gastrointestinal Tract

There are largely two factors at work here:

• digestive enzymes

• intestinal flora (commensals).

Digestive Enzymes

These are involved in the hydrolysis of conjugated chemical substances (remember: the conjugate group can be a sugar) so that the active ingredients are made available for entry into the bloodstream.

This process is capacity limited; in other words, there are only so many enzymes and when their sites are all taken up, and no longer available, the rest of the drug or remedy remains unconjugated, no matter how high the dose. The cells of the gastrointestinal tract lumen are not the only type of cells to have this function.

Intestinal Flora

Certain intestinal flora (commensals) can remove conjugate groups, returning the chemicals to their non-polar state and allowing them to be more easily absorbed by the cells of the gut wall. The composition of the microbes is important and can be adversely affected by:

• Diet: too much sugar can produce an overgrowth of the wrong type of microbe.

• Disease: can affect the lining of the gastrointestinal tract or the gastrointestinal environment.

• Drugs: antibiotics kill not only harmful bacteria but useful bacteria as well.

The correct balance of microbes in the gut is therefore the key factor in the enterohepatic cycle (see below). Healthy cells in the lumen are also important as there is some active transport of the unconjugated bile salts.

• Other Aspects of Intestinal Flora

The enzymes produced by intestinal bacteria synthesize vitamin K, biotin, folic acid, thiamine and vitamin B₁₂.

In individuals who are deficient in lactase (the enzyme responsible for breaking down the lactose in milk), the undigested lactose is fermented by bacteria residing in the colon. Fermentation can be vigorous fermentation, resulting in flatus and possibly diarrhoea.

Enterohepatic Cycle or Circulation

Some chemicals metabolized in the liver are excreted in the bile, which passes into the intestinal lumen, to be once again reabsorbed by the intestinal cells and returned to the liver (Figure 17.1). This enterohepatic circulation prolongs the time the drug can spend in the body, because it is recycled.

Figure 17.1 Detoxification pathways in the liver, showing removal and the enterohepatic cycle. (i) Drug is absorbed from the gastrointestinal tract, passing to the liver via the hepatic portal vein. (ii) Drug encounters phase I enzymes (variations of cytochrome p450), which prepare it for phase II. (iii) Phase II adds a compound to the drug (conjugation), making it more polar and therefore water soluble. (iv) Conjugated drug is recycled to the gastrointestinal tract, where bacteria cleave off conjugated compounds (the enterohepatic cycle). Some of the drug is removed from body via the faeces. (v) Conjugated, water-soluble drug passes to the kidney to be removed in urine (vi).

Conjugated compounds are polar and therefore require active uptake by the cells in the lumen of the gastrointestinal tract; unconjugated compounds are non-polar and are more easily absorbed by the non-polar bilipid cell membrane (see Chapter 3 ‘Bonds found in biological chemistry’, p. 24). When conjugated compounds are returned to the gastrointestinal tract, the conjugate group can be cleaved from the drug, allowing the non-polar drug to be reabsorbed. In the enterohepatic cycle, these conjugates are cleaved from the drug by the commensals (the microbes present in the small intestine).

Bile salts and cholesterol tend to be recirculated between the gut and the liver in this way, as do a variety of chemicals and drugs, for example:

• many steroids

• metabolites of vitamin D

• choramphenicol.

This phenomenon has been extensively studied with morphine, a lipid-soluble drug. Morphine becomes conjugated in the intestine but the intestinal flora is capable of removing the conjugate. This significantly prolongs the activity of morphine and, over a period time, increases the dosage in the body. Cardiac glycosides found in herbs such as Convallaria majalis and Crataegus species are involved in the same process.

It is very important to take the enterohepatic mechanism into consideration because it can maintain the concentration of a drug or remedy in the body, even increasing it with further ingestion. This results in the possibility of toxicity, although many drugs are designed to take advantage of this phenomenon.

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