Gene Related Metabolism of Drugs

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Gene Related Metabolism of Drugs

• Anastasios Maratonitis
• (2009)

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• There are more than 30 families of
  drug-metabolizing enzymes in humans, and
  essentially all have genetic variants, many of
  which translate into functional changes in the
  proteins encoded. The cytochrome P-450 enzymes, a
  superfamily of microsomal drug-metabolizing
  enzymes, are the most important of the enzymes
  that catalyze phase I drug metabolism. One member
  of this family, cytochrome P-450 2D6 (CYP2D6)
  will be used as example of gene variation in
  drug metabolism. More than 75 CYP2D6 alleles have
  been described, subjects with ultra rapid
  metabolism have been proven to have multiple
  copies of this gene. Such subjects can have an
  inadequate therapeutic response to standard doses
  of the drugs metabolized by CYP2D6 (the higher
  the metabolic ratio, the less metabolite is
  excreted). The effect of the number of copies of
  the CYP2D6 gene ranging from 0 to 13 is well
  visible on the pharmacokinetics of the
  antidepressant drug nortriptyline shown in next
  figure

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Although the occurrence of multiple copies of the
CYP2D6 gene is relatively infrequent among
northern Europeans, in East African populations,
the allele frequency can be as high as 29 percent

• Mean plasma concentrations of nortriptyline after
  a single 25-mg oral dose are shown in subjects
  with 0, 1, 2, 3, or 13 functional CYP2D6 genes

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The table below lists common drug metabolism gene
variants and their frequencies in major ethnic
groups.
Adapted from Blue Cross Blue Shield Special report
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• The CYP2D6 polymorphism represents an excellent
  example of both the potential clinical
  implications and the process by which gene
  research led from the phenotype to an
  understanding of molecular mechanisms at the
  level of the genotype. Similar approaches were
  subsequently applied to other families of
  drug-metabolizing enzymes. We now know that many
  other drug-metabolizing enzymes display genetic
  variation that can influence a person's response
  to a drug. The table bellow lists selected
  examples of those, clinically relevant,
  variations . In many cases, we also understand
  the molecular basis of inherited variation in the
  drug-metabolizing enzymes.

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• (GENE) DRUGS
  RESPONSES AFFECTED metabolizers
• CYP2C9
  Anticoagulant effect of warfarin
• CYP2C19
  Peptic ulcer response to omeprazole
• CYP3A4/3A5/3A7
  Efficacy of immunosuppressive effects of
  tacrolimus
• Dihydropyrimidine
  Fluorouracil neurotoxicity
• Dehydrogenase
• N-acetyltransferase
  Hypersensitivity to sulfonamides, amonafide
  toxicity,
  (NAT2)
  
  hydralazine-induced lupus, isoniazid
  neurotoxicity
• Glutathione transferases
  Decreased response in breast cancer, more
  toxicity (GSTM1, GSTT1, GSTP1)
  and worse response in acute myelogenous
  leukemia

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• P-glycoprotein
  Decreased CD4 response in HIV-infected
  (ABCB1) patients, decreased
  digoxin AUC, drug resistance in epilepsy
• UGT2B7
  Morphine plasma
  levels
• COMT
  Enhanced Levodopa drug
  effect
• CYP2B6
  Ovarian failure due to Cyclophosphamide
• Thiopurine methyltransferase
  Thiopurine toxicity and efficacy,
  (TPMT)
  risk of second
  cancers