PK

• 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

  
• 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)

  
• 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
• ABC transporter

  ABCB1 (ATP-binding cassette sub-family B member 1, also known as P-glycoprotein 1 or Pgp, as well as multidrug resistance protein 1 (MDR1)) Active transporters that are ATP-dependent, efflux pump
• Decreased P-glycoprotein expression

  May result in supratherapeutic plasma concentrations of relevant drugs and drug toxicity
• Solute-carrier (SLC) transporters

  SLCO1B1 Transporters: Statins are taken up from the bloodstream into the liver by SLCO1B1
• Individuals with reduced SLCO1B1 function in hepatocytes

  Increase simvastatin-induced myopathy
• Membrane-spanning proteins

  • Facilitate drug transport - across the gastrointestinal tract - drug excretion into the bile and urine - drug distribution across the blood-brain barrier - drug uptake into target cells
• Genetic variation for drug transport proteins may affect the distribution of drugs that are substrates for these proteins and alter drug concentrations at their therapeutic sites of action
• Transporter Super-families

  • ATP-binding cassette (ABC) transporters
  • Solute-carrier (SLC) transporters
• ABC Family - ABCB1 (ATP-binding cassette sub-family B member 1)

  Also known as P-glycoprotein 1 or P-gp, as well as multidrug resistance protein 1 (MDR1)
• SLC Family - SLCO1B1 (Solute carrier organic anion transporter family member 1B1)

  A protein that is encoded by the SLCO1B1 gene
• 1. glycoprotein

  • An ATP-dependent transmembrane efflux pump encoded by the ABCB1 gene (also called the multidrug resistance 1 gene, MDR1), which is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) transport superfamily
  • A glycoprotein and is the first recognized for its ability to actively export anticancer agents from cancer cells and promote multidrug resistance to many anticancer agents
  • Widely distributed in normal cell types, including intestinal enterocytes, hepatocytes, renal proximal tubule cells, and endothelial cells lining the blood-brain barrier, and serves a protective role by transporting toxic substances or metabolites out of cells (efflux transporter)
• Increased intestinal expression of P-glycoprotein

  Can limit the absorption of P-glycoprotein substrates, thus reducing their bioavailability and preventing the attainment of therapeutic plasma concentrations
• ABCB1 (P-gp) Transporter

  Active transport of drugs out of the cell by P-glycoprotein
• 1. glycoprotein is one of the most recognized drug transport proteins that exhibit genetic polymorphism
• Genetic variations of the expression and function of P-gp may result in differing susceptibility to a wide variety of drugs (e.g., anticancer agents, cardiac drugs, HIV protease inhibitors, immunosuppressants, etc.)
• Commonly studied ABCB1 variants

  • 3435C>T in exon 26
  • 2677G>T/A in exon 21
• SLCO1B1 gene


  Encodes for organic anion transporting polypeptide 1B1 (also called OATP1B1)
• SLCO1B1

  • An uptake transporter that is expressed on the basolateral membrane of hepatocytes, kidney epithelial cells, and brain capillary endothelial cells
  • Has a broad drug substrate spectrum, such as statins
• Statins


  Taken up from the bloodstream into the liver by SLCO1B1
• Statins are metabolized by phase I and II enzymes and eliminated via efflux transporters mediated biliary excretion
• Statin

  HMG-CoA reductase inhibitor that effectively lowers total and lowdensity lipoprotein cholesterol and reduces the risk for cardiovascular events in coronary heart disease
• Common SLCO1B1 Alleles

  • *1 (Normal function, Wild type)
  • *5, *15, *17 (Decreased function)
• SLCO1B1 Genotype and Phenotype

  • *1/*1 (Normal transporter function, Normal myopathy risk, Use standard dose)
  • *1/*5, *1/*15, *1/*17 (Intermediate transporter function, Intermediate myopathy risk, Use a lower dose or consider an alternative statin)
  • *5/*5, *5/*15, *5/*17, *15/*15, *17/*17 (Low transporter function, High myopathy risk, Use a lower dose or consider an alternative statin)