The biochemical basis of drug interactions
The biotransformation of a drug may either lead to the termination of its pharmacological activity or, occasionally, to its activation to a pharmacologically effective entity. It is also possible that a drug may be metabolized to form pharmacologically or toxicologically active metabolites. Whatever the outcome, the biotransformation of a drug ultimately involves its conversion to a more hydrophilic form thereby facilitating its excretion into the urine. However, some lipophilic drugs and their metabolites are excreted via the bile into the intestine while others, that are volatile, pass into the lungs and are thereby excreted in the expired air.
The biotransformation Phase 1 involves the oxidative catabolism of the drug. The end products of the phase 1 reactions are generally conjugated by uridine diphosphorylglucuronyl transferase, sulphatase or N-acetyltransferase to form polar, water-soluble products which are then excreted into the urine. These are the products of the phase 2 reactions. While it is well known that products of the phase 1 reactions are often pharmacologically active (for example, norfluoxetine which is a metabolic product of fluoxetine), it is also possible that the end product of phase 2 reactions can also be pharmacologically active. For example, morphine-6-glucuronide is as pharmacologically active as the parent compound. The primary site of biotransformation is the liver although the gastrointestinal tract, kidneys and the skin also contribute to a minor extent. Drugs that are orally administered often undergo first-pass metabolism. This involves their (generally partial) metabolism in the liver following their entry from the gastrointestinal tract via the portal circulation. This inevitably leads to a reduction in the effective blood concentration and must therefore be taken into account when the dose of the drug to be administered is calculated. In the liver, the microsomal enzymes that are responsible for catalysing the oxidative reactions are the cytochrome P450 family of enzymes. These enzymes are haem-containing membrane proteins that are bound to the smooth endoplasmic reticulum of the hepatocytes. Of the 12 gene families of the cytochrome P450 system that have been identified in man, those classified as cytochrome P450 types 1, 2 and 3 account for most of the drug biotransformations. In addition to the oxidative reactions undertaken by the P450 enzymes (also known as isozymes), hydrolytic reactions are carried out by epoxide hydrolase and several amidases, esterases, proteases and peptidases.
There are several important factors which may influence biotransformation reactions. Thus some drugs or toxins may induce the synthesis of microsomal oxidases by the liver (for example, a barbiturate) and thereby enhance the metabolism of the drug, or any other drug given concurrently which is metabolized by the same enzyme system (for example, warfarin). Nicotine in tobacco smoke is known to increase the activity of the cytochrome P450 1A2 isozyme which may predispose some individuals to a greater risk of cancer. Some drugs produce hepatotoxic metabolites which thereby impair the biotransformation of other drugs or toxins which may be present. For example, chronic alcohol intake can lead to the formation of hepatotoxic metabolites. Drugs may also selectively inhibit individual isozymes of the P450 system, thereby causing an unexpected rise in the blood and tissue concentrations of any drug given concurrently which is also metabolized by that isozyme. The SSRI antidepressants for example have been shown to act as inhibitors of some P450 isozymes, thereby not only reducing their own metabolism but also those of other drugs given concurrently. Some foods may also inhibit the P450 isozymes and thereby enhance the toxicity, or the duration and magnitude of the therapeutic response of a drug given concurrently. Grapefruit juice, for example, is a significant inhibitor of the P450 isozyme 3A4, an enzyme which is widely involved in the metabolism of psychotropic drugs. It is self-evident that biotransformation will be reduced in patients with liver or kidney disease, in the elderly and also in neonates. In addition, pharmacogenetic differences play a considerable role in the way an individual patient metabolizes a drug. Such differences often result from polymorphisms in the cytochrome P450 family of microsomal enzymes.
The biotransformation of a drug may either lead to the termination of its pharmacological activity or, occasionally, to its activation to a pharmacologically effective entity. It is also possible that a drug may be metabolized to form pharmacologically or toxicologically active metabolites. Whatever the outcome, the biotransformation of a drug ultimately involves its conversion to a more hydrophilic form thereby facilitating its excretion into the urine. However, some lipophilic drugs and their metabolites are excreted via the bile into the intestine while others, that are volatile, pass into the lungs and are thereby excreted in the expired air.
The biotransformation Phase 1 involves the oxidative catabolism of the drug. The end products of the phase 1 reactions are generally conjugated by uridine diphosphorylglucuronyl transferase, sulphatase or N-acetyltransferase to form polar, water-soluble products which are then excreted into the urine. These are the products of the phase 2 reactions. While it is well known that products of the phase 1 reactions are often pharmacologically active (for example, norfluoxetine which is a metabolic product of fluoxetine), it is also possible that the end product of phase 2 reactions can also be pharmacologically active. For example, morphine-6-glucuronide is as pharmacologically active as the parent compound. The primary site of biotransformation is the liver although the gastrointestinal tract, kidneys and the skin also contribute to a minor extent. Drugs that are orally administered often undergo first-pass metabolism. This involves their (generally partial) metabolism in the liver following their entry from the gastrointestinal tract via the portal circulation. This inevitably leads to a reduction in the effective blood concentration and must therefore be taken into account when the dose of the drug to be administered is calculated. In the liver, the microsomal enzymes that are responsible for catalysing the oxidative reactions are the cytochrome P450 family of enzymes. These enzymes are haem-containing membrane proteins that are bound to the smooth endoplasmic reticulum of the hepatocytes. Of the 12 gene families of the cytochrome P450 system that have been identified in man, those classified as cytochrome P450 types 1, 2 and 3 account for most of the drug biotransformations. In addition to the oxidative reactions undertaken by the P450 enzymes (also known as isozymes), hydrolytic reactions are carried out by epoxide hydrolase and several amidases, esterases, proteases and peptidases.
There are several important factors which may influence biotransformation reactions. Thus some drugs or toxins may induce the synthesis of microsomal oxidases by the liver (for example, a barbiturate) and thereby enhance the metabolism of the drug, or any other drug given concurrently which is metabolized by the same enzyme system (for example, warfarin). Nicotine in tobacco smoke is known to increase the activity of the cytochrome P450 1A2 isozyme which may predispose some individuals to a greater risk of cancer. Some drugs produce hepatotoxic metabolites which thereby impair the biotransformation of other drugs or toxins which may be present. For example, chronic alcohol intake can lead to the formation of hepatotoxic metabolites. Drugs may also selectively inhibit individual isozymes of the P450 system, thereby causing an unexpected rise in the blood and tissue concentrations of any drug given concurrently which is also metabolized by that isozyme. The SSRI antidepressants for example have been shown to act as inhibitors of some P450 isozymes, thereby not only reducing their own metabolism but also those of other drugs given concurrently. Some foods may also inhibit the P450 isozymes and thereby enhance the toxicity, or the duration and magnitude of the therapeutic response of a drug given concurrently. Grapefruit juice, for example, is a significant inhibitor of the P450 isozyme 3A4, an enzyme which is widely involved in the metabolism of psychotropic drugs. It is self-evident that biotransformation will be reduced in patients with liver or kidney disease, in the elderly and also in neonates. In addition, pharmacogenetic differences play a considerable role in the way an individual patient metabolizes a drug. Such differences often result from polymorphisms in the cytochrome P450 family of microsomal enzymes.
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