Genetic polymorphism
In pharmacokinetics, genetic polymorphism refers to differences between individuals’ ability to metabolize drugs. More than 25 years ago it was shown that the steady-state plasma concentration of the TCA nortriptyline was related to the genetic characteristics of the patient. Thus homozygous, but not heterozygous, twins had similar blood nortriptyline concentrations. Since that time it has become clear that many of the liver enzymes concerned with drug metabolism exhibit genetic polymorphism. This may be particularly important when depressed patients receiving antidepressant therapy are also given other drugs which compete for the same hepatic enzyme. The most important group of liver enzymes that are responsible for the oxidative metabolism of most drugs are the microsomal cytochrome P450 oxidases. There are many subtypes (termed isozymes). Each cytochrome P450 isoenzyme is the product of a separate gene, and so far more than 200 such genes have been identified. Furthermore, a number of cytochrome P450 genes have been shown to have different alleles which have resulted from mutation. Where such a mutation exists in more than 1% of the population, the term ‘‘genetic polymorphism’’ is applied. Many of the polymorphic forms of the cytochrome P450 enzyme appear to be of minor significance in drug metabolism. In some individuals an isoenzyme may be absent. This is an inherited trait which can vary in incidence according to racial background. Depending on whether the isoenzyme is absent or present, individuals are classified as extensive or poor metabolizers of the reference compound. The clinical importance of genetic polymorphism depends on factors such as the health status of the patient and the concomitant administration of any drugs which might act as a substrate or inhibitor of a particular isoenzyme. For example, a depressed patient who metabolizes an SSRI (selective serotonin reuptake inhibitor) slowly will have higher plasma concentrations of that drug than another patient who metabolizes the drug at the norma l rate. However, this is unlikely to be clinically significant given the high therapeutic index of the SSRIs. In contrast, TCAs have a low therapeutic index and the active metabolites of amitriptyline (nortriptyline) and imipramine (desipramine) are usually hydroxylated via the cytochrome P450 2D6 pathway. Slow metabolizers of desmethylated TCAs will experience TCA accumulation, which may result in potentially toxic cardiovascular effects. Conversely, patients who are fast metabolizers may experience subtherapeutic plasma drug concentrations. Another factor which should be considered is the relative importance of the defective metabolic pathway in the overall metabolism of a drug. For example, paroxetine is metabolized by at least two pathways and the suboptimal activity of one enzyme has a relatively minor effect on the elimination of the drug. For the other SSRIs, the hepatic enzymes responsible for oxidization have not been clearly identified. However, these agents have a high affinity for the cytochrome P450 system and drug–drug interactions may be important under certain circumstances.
In pharmacokinetics, genetic polymorphism refers to differences between individuals’ ability to metabolize drugs. More than 25 years ago it was shown that the steady-state plasma concentration of the TCA nortriptyline was related to the genetic characteristics of the patient. Thus homozygous, but not heterozygous, twins had similar blood nortriptyline concentrations. Since that time it has become clear that many of the liver enzymes concerned with drug metabolism exhibit genetic polymorphism. This may be particularly important when depressed patients receiving antidepressant therapy are also given other drugs which compete for the same hepatic enzyme. The most important group of liver enzymes that are responsible for the oxidative metabolism of most drugs are the microsomal cytochrome P450 oxidases. There are many subtypes (termed isozymes). Each cytochrome P450 isoenzyme is the product of a separate gene, and so far more than 200 such genes have been identified. Furthermore, a number of cytochrome P450 genes have been shown to have different alleles which have resulted from mutation. Where such a mutation exists in more than 1% of the population, the term ‘‘genetic polymorphism’’ is applied. Many of the polymorphic forms of the cytochrome P450 enzyme appear to be of minor significance in drug metabolism. In some individuals an isoenzyme may be absent. This is an inherited trait which can vary in incidence according to racial background. Depending on whether the isoenzyme is absent or present, individuals are classified as extensive or poor metabolizers of the reference compound. The clinical importance of genetic polymorphism depends on factors such as the health status of the patient and the concomitant administration of any drugs which might act as a substrate or inhibitor of a particular isoenzyme. For example, a depressed patient who metabolizes an SSRI (selective serotonin reuptake inhibitor) slowly will have higher plasma concentrations of that drug than another patient who metabolizes the drug at the norma l rate. However, this is unlikely to be clinically significant given the high therapeutic index of the SSRIs. In contrast, TCAs have a low therapeutic index and the active metabolites of amitriptyline (nortriptyline) and imipramine (desipramine) are usually hydroxylated via the cytochrome P450 2D6 pathway. Slow metabolizers of desmethylated TCAs will experience TCA accumulation, which may result in potentially toxic cardiovascular effects. Conversely, patients who are fast metabolizers may experience subtherapeutic plasma drug concentrations. Another factor which should be considered is the relative importance of the defective metabolic pathway in the overall metabolism of a drug. For example, paroxetine is metabolized by at least two pathways and the suboptimal activity of one enzyme has a relatively minor effect on the elimination of the drug. For the other SSRIs, the hepatic enzymes responsible for oxidization have not been clearly identified. However, these agents have a high affinity for the cytochrome P450 system and drug–drug interactions may be important under certain circumstances.
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