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• Pharmacogenomics


  Study of how an individual's genetic makeup affects their response to drugs
• Phase II metabolizing enzymes

  • UGT1A1 (UDP-glucuronosyl transferases 1A1)
  • TPMT (Thiopurine methyl transferase)
  • NAT2 (N-acetyl transferase 2)

  
• UGT1A1


  • Responsible for the glucuronidation of bilirubin from its toxic form (unconjugated bilirubin) to its nontoxic form (conjugated bilirubin), allowing for its excretion from the body
  • Catalyzes the glucuronidation reaction to render drugs and endogenous compounds (e.g., bilirubin, estrogens, thyroid hormone) water-soluble molecules for biliary or renal elimination

  
• UGT1A1 polymorphism


  • UGT1A1*1 allele is wild type/normal function allele
  • UGT1A1*6, *28, and *37 alleles are the most common ones that result in reduced enzymatic activity of UGT1A1
  • UGT1A1*28 allele is common in many ethnic groups: Africans (42-56%), Caucasians (26-39%), Asians (9-16%)
• UGT1A1 deficiency


  Decreases SN-38 clearance, thereby increasing its half-life, which leads to severe toxicity
• Irinotecan


  An anticancer agent widely used for the treatment of solid tumors, including colorectal, lung, and pancreatic cancers

  
• Irinotecan metabolism


  1. Irinotecan is a prodrug and is activated by carboxylesterase (CE) to SN-38, a potent topoisomerase I inhibitor

  2. SN-38 is converted to an inactive metabolite SN-38-G by glucuronidation via polymorphic UGT1A1

  3. SN-38-G undergoes biliary excretion into the GI tract

  
• UGT1A1*28 allele


  Contains seven TA repeats in the promoter, and this extra TA repeat results in decreased UGT1A1 transcription efficiency, leading to reduced UGT1A1 expression
• UGT1A1*28 (TA7) allele


  Metabolizes irinotecan slowly with an increased risk of toxicity including high-grade neutropenia and diarrhea

  
• Atazanavir


  An antiretroviral (Anti-HIV) drug
• Atazanavir


  Inhibits hepatic UGT1A1, which can result in increased plasma unconjugated (indirect) bilirubin concentrations, presenting as jaundice in some patients

  
• TPMT


  Thiopurine S-methyltransferase, an enzyme that breaks down a class of drugs called thiopurines

  
• Common TPMT alleles


  • TPMT*1 (wild type/normal function)
  • TPMT*3A (most common in whites)
  • TPMT*2
  • TPMT*3B
  • TPMT*3C

  
• Patients homozygous for no-functional TPMT variants

  Are at increased risk for life-threatening myelosuppression when treated at conventional doses of Thiopurines

  
• Thiopurines


  Drugs such as azathioprine, 6-mercaptopurine, and 6-thioguanine that interfere with nucleic acid synthesis, used to treat lymphoblastic leukemia, autoimmune disease, and inflammatory bowel disease

  
• Thiopurine metabolism


  1. TPMT catalyzes inactivation of 6-mercaptopurine (6-MP)

  2. TPMT deficiency leads to decreased clearance of 6-MP, which exerts toxicity including myelosuppression and hepatotoxicity

  
• NAT2


  1. acetyl transferase 2, involved in the acetylation of a variety of therapeutic agents
• NAT2 phenotypes


  • Slow acetylator (has two slow alleles)
  • Fast/Rapid acetylator (has two wild type alleles)
  • Intermediate acetylator (has one wild type and one slow allele)
• Isoniazid (INH)


  The most widely used chemotherapeutic agent for the treatment of tuberculosis (TB)
• Isoniazid metabolism


  1. Isoniazid is a prodrug and must be activated by bacterial catalase

  2. The activated INH inhibits bacterial cell walls

  3. Isoniazid is metabolized by N-Acetyl Transferase type 2 (NAT2) in the liver to N-acetyl isoniazid (inactive form) by acetylation

  
• Patients with slow acetylator NAT2 activity


  Are at greater risk of experiencing isoniazid-induced hepatotoxicity and neurotoxicity

  
• Slow acetylation may lead to higher blood levels of isoniazid, and thus, an increase in toxic reactions