Week 6

• Metabolism


  The process by which a drug (or other compound) is chemically converted in the body into another substance (or other substances) normally for the purpose of excretion
• The relative importance of metabolic and renal clearance differs, depending on the drug
• Some drugs undergo mainly metabolic clearance, and others undergo mainly renal clearance
• Lipid solubility or degree of ionisation


  One of the key factors which determine the importance of hepatic versus renal clearance
• As cell membranes are lipid in nature, lipid soluble, also known as un-ionised, drugs can readily cross them
• These drugs will enter hepatocytes (liver cells) and are likely to undergo extensive hepatic clearance
• If a drug is ionised, it will not be able to cross the membranes of liver cells easily
• Drug metabolism


  The process by which a drug is chemically converted in the body into another substance (or other substances) normally for the purpose of excretion
• Elimination and clearance


  RE = CL x C, where CL is a proportionality constant which relates rate of elimination of a drug from the body to its concentration at site of measurement
• Clsystemic


  Clliver + Clkidney + ... + Clother
• Liver clearance occurs by metabolism and/or biliary elimination
• Metabolism converts lipophilic compounds that are generally readily absorbed into hydrophilic compounds that are generally readily excreted
• Metabolism primarily takes place in the liver, but can occur in other tissues, including those of the gastrointestinal tract, lungs, kidneys and skin
• Phase 1 metabolism


  Functionalisation reactions - introducing or revealing a functional group the molecule
• Phase 2 metabolism

  Conjugation reactions
• Phase 1 and Phase 2 normally decrease the lipid solubility of the drug
• Phase 1 reactions


  • Often are oxidation, hydrolysis, hydration or a variety of other reactions
  • In phase 1 metabolism a functional group is exposed or added to the drug molecule so it can serve as a substrate for phase 2 reactions
  • In phase 1 metabolism the polarity of the molecule is generally increased, and hence its hydrophilicity
  • Phase 1 metabolism also makes the molecule more likely to be reactive, because of the functional group
  • Many drugs have more than one route of phase 1 metabolism
• Phase 2 metabolism


  • The conjugation of the phase 1 metabolite with a highly polar group arising from an endogenous compounds
  • Phase 2 metabolism is often glucuronidation, sulfation, methylation, acetylation, amino acid conjugation and glutathione conjugation reactions
  • The result of phase 2 metabolism is a large increase in hydrophilicity
  • Phase 2 metabolism often results in a decrease in toxicity
• Phase 1 and 2 reactions


  • Phase 1 reactions can generally be considered as providing a substrate for phase 2 reactions, and for an increase in hydrophilicity
  • Phase 2 reactions are thought of as the principal detoxification step, but detoxification sometimes does not occur
  • Not all drugs are metabolised
  • Not all drugs are metabolised in this sequential manner
• Possible outcomes of metabolism


  • An active drug can be converted to a less or non-active metabolite
  • An inactive drug (prodrug) can be converted to an active drug
  • An active drug can be converted to an active metabolite
  • An active drug can be converted to a toxic metabolite
• Cytochrome P450 enzymes


  The most common enzymes involved in drug biotransformation, accounting for about 75% of total drug metabolism
• Tissues associated with drug metabolism


  • Liver
  • Skin
  • Lungs
  • Nasal mucosa
  • Eye
  • Gastrointestinal tract
  • Kidney
  • Adrenal
  • Pancreas
  • Spleen
  • Heart
  • Brain
  • Testis
  • Ovary
  • Placenta
  • Plasma
  • Erythrocytes
  • Platelets
  • Lymphocytes
  • Aorta
• Phase 1 enzymes


  • Cytochrome P540 enzymes
  • Alcohol dehydrogenase
  • Aldehyde dehydrogenase
  • Xanthine oxidase
  • Amine oxidases
  • Aromatases
  • Alkyl hydrazine oxidases
• Phase 2 enzymes

  • UDP-glucuronosyltransferase (UGT)
  • Sulfotransferase
  • Methyltransferase
  • Acetyltransferase
  • Acyl synthetase
  • Glutathione-S-transferase
• We possess a relatively small number of enzymes, which have very broad substrate specificities, some of which also metabolise endogenous compounds
• The broad substrate specificities also mean that some enzyme substrate specificities overlap
• Implications of broad substrate specificity


  • Competition between drugs for the same enzyme (drug/drug interactions)
  • Competition between a drug and an endogenous or exogenous compound for the same enzyme (drug/compound interaction)
  • Competition between enzymes for a substrate (drug/compound can undergo metabolism down different pathways to produce multiple metabolites)
• Enzyme induction


  Increased metabolism and decreases pharmacological action of a drug that is normally a substrate for that enzyme
• Enzyme inhibition


  Decreases metabolism and increased pharmacological action of a drug that is normally a substrate for that enzyme
• Enzyme induction


  • More (or more active) metabolising enzymes
  • Most cases lead to decreased magnitude and duration of effect for drugs that are substrates of that enzyme
  • Mechanisms include increased synthesis, decreased degradation, increased activation or a combination
  • Usually a lag time in development
  • Some inducers will induce specific isoenzymes others a range of isoenzymes
  • Liver is the major target for enzyme induction although extra-hepatic induction also occurs (e.g. gastrointestinal tract, lung, etc.)
• Enzyme inhibition


  • Less active metabolising enzymes
  • Leads to higher concentrations of drugs that are substrates for that enzyme and a higher incidence of side effects and toxic effects
  • A drug may be a substrate for one isoform, and an inhibitor of another
  • Inhibition may be due to binding of the parent drug or a metabolite to the enzyme isoform reducing its metabolic activity
  • Inhibitors may be present in food and drinks (e.g. grapefruit juice, isosafrole, safrole)
  • Metabolic inhibition can also lead to reduced production of active metabolites from prodrugs
• Enzyme autoinduction


  Autoinduction in drug metabolism occurs when a drug induces the enzymes responsible for its own metabolism
• Physiology of biliary excretion


  • Bile flow rate is approximately 800-1000mL/day
  • Bile secretion into the duodenum is under the control of various factors
• Factors controlling bile secretion into duodenum


  1. Fats in the lumen of the duodenum

  2. Acid content in duodenum

  3. GI peristaltic action
• Bile acids


  • Synthesised from cholesterol in the liver and formed into bile salts which are stored in the gallbladder
  • Amphipathic compounds (contain both hydrophilic and hydrophobic regions)
  • Enable bile acids to solubilize lipids, fatty acids, cholesterol and very lipophilic compounds into micelles -> enhancing absorption (incl. for some drugs e.g., isotretinoin)
  • Approximately 95% of bile acids secreted into the duodenum are reabsorbed in the ileum
• Emptying of the gallbladder


  • Typically the gallbladder may only empty once or twice per day (depending on a persons fatty food intake)
  • The time of emptying is individual specific and varies greatly between individuals
• Biliary extraction, enterohepatic recirculation and biliary elimination


  Impact on drug pharmacokinetics and pharmacodynamics
• Enterohepatic cycling (EHC)


  • Following an oral dose of a drug a fraction of the dose: Absorbs across the gut wall, into the blood stream
  • Where its transported via the portal vein to the liver
  • When the drug enters the liver, some of it may be metabolised (optional)
  • A fraction of the drug or drug metabolite may be excreted into the gallbladder with bile
  • The drug or drug metabolite is excreted from the gallbladder with the bile into the lumen of the small intestine
  • Intestinal enzymes or gut bacteria may cleave the glucuronide metabolite to generate the parent drug again (optional)
  • Drug may be re-absorbed from the gut lumen. If the drug is reabsorbed the cycle may begin again
• Importance of enterohepatic cycling


  • If the fraction of drug that undergoes biliary excretion is minimal enterohepatic cycling will be insignificant
  • If following biliary excretion the drug is readily degraded in the gut lumen or has poor reabsorption characteristics -> biliary elimination will be more significant than enterohepatic cycling
  • Importance of enterohepatic cycling is related to the fraction of drug that undergoes biliary excretion and the availability of this amount to be reabsorbed
• Features of a drug that favours biliary excretion


  • Polar
  • Molecular weight exceeds 500 Daltons
  • Glucuronide conjugates are most likely to undergo EHC (also glycosides and sulphates)