WEEK 4: DRUG BIOTRANSFORMATION

• Drug biotransformation


  Chemical reactions which occur in the body and lead to change of drugs from lipid soluble form to water soluble form that is easily excreted
• First pass effect


  Phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the site of action or systemic circulation
• ROA subject to first pass effects


  • Oral
  • Rectal
  • Inhalation
• ROA not subject to first pass effects


  • Parenteral ROA
  • Topical ROA
• Metabolism


  Increases the renal excretion
• Organ sites of drug metabolism


  • Liver
  • Kidney
  • Skin
  • Lungs
  • Intestine
  • Brain
  • Blood plasma
• Enzymes in gut mucosa


  • Monoamine oxidase (serotonin + catecholamines)
  • Sulphatase
• Enzymes in gut lumen

  • Glucoronidase
  • Azoreductase (N=N)
• Enzymes in plasma


  • Catechol O-Methyl Transferase (COMT)
  • Esterase
  • Amidase
• Microsomes


  Located in smooth endoplasmic reticulum, catalyze Phase I and Phase II (glucuronidation), inducible by drugs, e.g. Cytochrome P450, UDP glucoronosyl transferases (UGT), epoxide hydrolases
• Overview of hepatic metabolic reactions


  1. Phase I (functionalization reactions): Involves introduction of polar functions (-NH2, -OH, -SH), increase in water solubility, microsomal enzyme: predominantly CYP450

  2. Phase II (conjugation reactions): Involves conjugation preexisting functionality (-sulfate, -glutathione, -acyl/methyl groups), further enhances water solubility, UGT, Methyl / N-acetyl / Sulpho-transferase
• Phase I metabolism


  • Microsomal oxidation: Aliphatic or aromatic hydroxylation, N-, or S-oxidation, N-, O-, S-dealkylation
  • Non-microsomal oxidation: Oxidase (Monoamine Oxidase, Xanthine Oxidase, Diamine Oxidase), Dehydrogenase (Alcohol dehydrogenase, Aldehyde dehydrogenase)
• Phase I metabolism: Reduction


  • Microsomal reduction: Nitro-reduction, Azo-reduction, Decarboxylase
  • Non-microsomal reduction
• Phase I metabolism: Hydrolysis


  • Non-microsomal hydrolysis: Ester hydrolysis, Amide hydrolysis
• Cytochrome P450 (CYP450)


  Total 18 families in mammals, Family 1-3: metabolise xenobiotics, Family > 4: metabolise endogenous compounds, CYP3A metabolises > 50% of drugs, CYP2D6 famous for polymorphisms (codeine)
• Possible outcomes of Phase I reactions


  • Activation of pro-drug
  • Conversion of active drug to active metabolite
  • Termination of actions
  • Conversion of non-toxic drug to toxic metabolite
• Phase II metabolism


  • UGT: UDP-glucuronosyl-transferase
  • GST: Glutathione-S-transferase
  • NAT: N-acetyl-transferase
  • SULT: Sulfo-transferase
• Glucuronidation


  Microsomal enzyme, Glucoronic acid from endogenously synthesized uridine-5'-diphospho-α-D-glucuronic acid (UDP-GA), Substrates are called aglycones, Products are called glucoronides
• Sulfation


  Non-microsomal enzyme, Endogenous donor molecule: 3'-phosphodenosine-5'-phosphosulfate (PAPS), Substrates example: acetaminophen, minoxidil
• Acetylation


  Non-microsomal enzyme, Endogenous donor molecule: Acetyl coenzyme A, Substrates example: Isoniazid, sulfanilamide
• Methylation


  Non-microsomal (cytosolic) enzyme, Endogenous donor molecule: S-Adenosylmethionine (SAM), Substrates example: NE by PNMT and NE/ Epi/ Dopa by COMT
• A 72-year-old patient presented to HASA emergency department (ED) with muscle pain in both legs and cramps in his calves. He complains of tea-colored urine and an irregular heartbeat in the past three days. Five months prior to this present
• Aglycones


  Products of phase II metabolism
• Glucoronides


  Products of phase II metabolism
• PHASE II METABOLISM : SULFATION


  1. Non-microsomal enzyme

  2. Endogenous donor molecule: 3'-phosphodenosine-5'-phosphosulfate (PAPS)

  3. Substrates example: acetaminophen, minoxidil
• PHASE II METABOLISM : ACETYLATION


  1. Non-microsomal enzyme

  2. Endogenous donor molecule: Acetyl coenzyme A

  3. Substrates example: Isoniazid, sulfanilamide
• PHASE II METABOLISM : METHYLATION


  1. Non-microsomal (cytosolic) enzyme

  2. Endogenous donor molecule: S-Adenosylmethionine (SAM)

  3. Substrates example: NE by PNMT and NE/ Epi/ Dopa by COMT
• What is the difference between phase I and phase II reactions?
• What type of enzymes are involved in each phase?
• Name two common examples of phase I and phase II enzymes.
• 72-year-old patient


  • Presented to HASA emergency department (ED) with muscle pain in both legs and cramps in his calves
  • Complained of tea-colored urine and an irregular heartbeat in the past three days
  • Five months prior had been hospitalized due to Acute Coronary Syndrome (ACS) followed by a successful coronary intervention of a high-grade left anterior descending artery stenosis with percutaneous transluminal coronary angioplasty and drug-eluting stent implantation
  • Medication upon current presentation: acetylsalicylic acid 100 mg OD, ticagrelor 90 mg BD, ramipril 2.5 mg BD, pantoprazole 20 mg OD, and atorvastatin 20 mg ON
• Discuss any confounding factors that trigger his conditions that the physician diagnosed as rhabdomyolysis.
• Enzyme induction


  • The process of enzyme induction requires new protein synthesis, it takes several days or weeks after starting an enzyme-inducing agent to see the effects
  • Enzyme induction results in a decrease pharmacological effect or risk of therapeutic failure
  • If the affected drug has active metabolites, this may lead to an increased pharmacological/ adverse effect
• Drugs affected by CYP3A4 induction


  • Oral contraceptive (EE)
  • Corticosteroids
  • Ciclosporin
• Drugs affected by CYP2C9 induction


  • Diclofenac (Pain killer)
  • Losartan
  • Statins
• Enzyme inhibition


  • Many drugs act as inhibitors of cytochrome 450 enzymes (CYP450)
  • Enzyme inhibition leads to reduced metabolism of the drug and hence an increase in the steady-state drug concentration
  • Maximal effects can be seen within few days for drugs with short half-life and can be delayed for drugs with a long half-life
• Strength of enzyme inhibition


  • Strong inhibitors (AUC values: ≥ 5 fold increase, ≥ 80% decrease)
  • Moderate inhibitor (AUC values: ≥ 2 but <5 fold increase, 50-80% decrease)
  • Weak inhibitor (AUC values: ≥ 1.25 – 2 fold increase, 20-50% decrease)
• Example of enzyme inducers


  • Chronic alcohol consumption with acetaminophen
• Example of enzyme inhibitors


  • Clarithromycin
  • Ciprofloxacin (inhibit CYP3A4, increased anticoagulant effect which cause high risk of bleeding)
  • Grapefruit juice (inhibit CYP3A, increased pharmacological /adverse effect)
• Example of CYP2C19 inhibitor


  • Omeprazole (reduced anti-platelet effect of clopidogrel due to pro-drug)