| The response to any particular drug will be influenced by the kinetic properties of the drug (pharmacokinetics) and its effects (pharmacodynamics). Genes which code for drug-metabolizing enzymes, receptors and transporters can influence the individual's response to the drug and any variability in these genes may lead to inter-individual differences in response to that drug.
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| Pharmacogenomics studies the effects of genetic heterogeneity on drug responsiveness
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| Since the liver has a central role in drug metabolism, the pharmacogenomics of some hepatic drug-metabolizing enzymes, specifically the cytochrome P450 oxidases, is clinically relevant.
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| ALCOHOL-RELATED LIVER DISEASE |
| A 45-year-old businessman had a routine medical examination, at which he was found to have a slightly enlarged liver. Tests reveal: bilirubin 15 μmol/L (0.9 mg/dL), AST 434 U/L, ALT 198 U/L, ALP 300 U/L, γ-glutamyl transpeptidase (γGT) 950 U/L, and albumin 40 g/L (4 g/dL). He seemed perfectly well. |
| Comment. The patient has liver disease. On the basis of the biochemical tests there is evidence of hepatocellular damage. The increased γGT concentration is one of the most sensitive indices of excessive intake but there may also be enlarged red blood cells (macrocytosis) and an increased serum uric acid concentration. Patients may deny alcohol abuse. Needle biopsy of the liver may be necessary for diagnosis. In this patient microscopic examination of the tissue revealed characteristic changes of alcoholic steatosis, hepatitis and central fibrosis. This may be the forerunner of cirrhosis and the patient should abstain from alcohol. Other causes, such as chronic viral infection of the liver or an autoimmune active chronic hepatitis can be detected by blood tests. For reference ranges see Table 28.2. |
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| CYP2D6 is responsible for the metabolism of more than 100 pharmaceuticals, and a polymorphism of this enzyme is responsible for the long-established variation in the metabolism of debrisoquine, mentioned above. Patients are classified as ultra-rapid, extensive, intermediate and poor metabolizers of debrisoquine. There is one CYP2D6 genetic locus, and individuals may have two, one or no functional alleles, corresponding to extensive, intermediate and poor metabolizers respectively: gene multiplication can lead to three functional alleles and the ultra-rapid metabolizer
phenotype. Seventy five CYP2D6 alleleic variants have been identified and pharmacogenetic techniques can identify the metabolize phenotype, thereby predicting clinical response to treatment. Although debrisoquine is now obsolete, the CYP2D6 polymorphism is relevant for some drugs used in cardiac and psychiatric practice, since poor metabolizers are more likely than other individuals to experience drug toxicity, and less likely to gain benefit from the analgesic codeine, a pro-drug which is metabolized by CYP2D6 to morphine, the active drug. A polymorphism of CYP2C19, again leading to extensive and poor metabolize phenotypes, affects the metabolism of the proton pump inhibitor drugs used to gastro-esophageal reflux disease and the cure rate of treatment.
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