A/Prof. Ken Rodgers School of Life Sciences

Learning Objectives

  • Understand the concept of prodrugs
  • Outline how the metabolism and/or excretion of a drug may be influenced by the physicochemical properties of the drug
  • Describe the basic mechanisms of Phase 1 and Phase 2 reactions
  • Outline the mechanisms involved in renal and biliary elimination of drugs
  • Describe how enterohepatic recirculation prolongs the duration of action of drugs

References

  • Rang HP, Dale MM, Ritter JM,  Flower R and Henderson G (2015) Pharmacology, 8th Edition, Churchill Livingstone, Sydney.
  • Drug metabolism and elimination – Chapter 9

Drug Elimination

  • Irreversible loss of drug from the body is a combination of 2 processes
    • Metabolism
    • Excretion

Drug Metabolism: Outline

Drug metabolism: definition

  • Metabolism – Enzymic conversion of one chemical entity to another in the body
  • Before excretion through the urine, most drugs undergo metabolism in the liver
Phase 1 Reactions

Drug metabolism

Drug Metabolism

  • Terminates drug action (treated as a xenobiotic)
  • Allows for more rapid elimination of drug
  • Most occurs in the liver via microsomal (smooth endoplasmic reticulum) and non-microsomal (mitochondria, soluble) enzymatic reactions
  • Lipophilic drugs have polar / charged groups added in liver

Phases of Drug Metabolism

  • Metabolism involves two types of biochemical reaction
    • Phase 1 reactions (predominate)
      • Oxidation, reduction, or hydrolysis
      • Catabolic reactions (breakdown)
      • Generate or expose a functional/reactive group. Products can be more reactive or toxic than precursor
    • Phase 2 reactions
      • Conjugation with hydrophilic groups
      • Anabolic reactions (build up)
      • Usually results in inactive compounds

Drug Metabolism: Phase 1

Drug Metabolism: Phase 1

  • Phase 1 reactions
  • Often involve mixed function oxidase system
    • Cytochrome P-450 plays most important role
  • Often introduce a reactive group to the molecule
  • Adds or exposes functional groups (eg. -OH, -SH, -NH2, -COOH) allowing excretion or permitting compound to undergo phase II reactions

Examples of Phase 1 Reactions

Phase 1 Reactions

Cytochrome P450 structure

  • P450 are heme-containing proteins.
  • Polypeptide chains vary among CYPs and offer substrate specificity
  • Basic reaction:
  • Mono-oxygenation by one atom of oxygen into the substrate. The other oxygen atom is reduced to water
  • Substrate (RH) + O2 + NADPH + H+ –––> Product (ROH) + H20 + NADP+

Activation of prodrugs

Bioactivation of prodrug (inactive) to active metabolite

Activation of prodrugs

Drug Metabolism: Phase 2

Drug metabolism: Phase 2

  • Phase II reactions
    • Biosynthetic reactions (require energy) where compound or phase I-derived metabolite is covalently linked to an endogenous molecule (conjugate)
    • Conjugate = glucuronic acid, amino acids, glutathione, sulphate, methyl, or acetyl groups
    • Conjugation (eg hydroxyl, thiol, amino group)
    • Makes the drug less lipid soluble (highly polar) and more readily excreted in the urine and bile

Phase 2 reactions

Phase 2 reactions

Metabolism 3

Drug metabolism 8

  • Pathways
    • Phase 1 only
    • Phase 2 only
    • Phase 1 followed by Phase 2

Drug metabolism

Biotransformation in hepatocytes

  • Most occurs in the liver via microsomal (smooth endoplasmic reticulum) and non-microsomal (mitochondria, soluble) enzymatic reactions

Codeine pharmacokinetics (Martindale)

  • Codeine and its salts are absorbed from the gastrointestinal tract. Ingestion of codeine phosphate produces peak plasma codeine concentrations in about one hour.
  • Codeine is metabolised by O– and N-demethylation in the liver to morphine, norcodeine, and other metabolites. Metabolism to morphine is mediated by the cytochrome P450 isoenzyme CYP2D6, which shows genetic polymorphism.
  • Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid.
  • The plasma half-life has been reported to be between 3 and 4 hours after an oral or intramuscular dose.
  • Codeine crosses the placenta and is distributed into breast milk.

Drug excretion 1 (kidney)

Renal Excretion

Renal excretion

  • Nearly all drugs cross the glomerular filter freely
  • They will be efficiently excreted (ie. remain in tubular fluid) unless they are lipid soluble and can be re-absorbed into the blood
  • The key function of metabolism is to make the drug molecule less lipid soluble (more water soluble/more charged)
  • Drugs excreted unchanged: digoxin gentamicin, methotrexate

Drug excretion 3

  • Renal excretion
  • Protein bound drugs and large molecules such as heparin (anticoagulant) are not filtered
  • 80% of plasma is unfiltered and is present in peritubular capillaries of the proximal tubule
  • Two non-selective (acid/base) carrier systems actively secrete weak acids (OAT) and bases (OCT) into the renal tubule, and thus they are more rapidly excreted
    • Not restricted by plasma protein binding (highly efficient, so easily removed from binding site)
    • Potential for competition between two drugs
    • May be useful eg probenecid competes with penicillin for secretion, so prolonged penicillin t1/2

Drug excretion 4

Drug excretion 5

Drug excretion

Drug excretion 6

  • Ionised drugs (which are filtered or actively secreted in proximal tubule) undergo little reabsorption and are excreted
  • Lipophilic drugs diffuse back (reabsorbed) into blood therefore not eliminated
  • Drugs bound to plasma proteins are unable to be filtered but are subject to tubular secretion (eg. penicillin)

Drug excretion 7

  • Most drugs undergo
    • a) glomerular filtration
    • b) partial tubular reabsorption
  • Some only undergo
    • c) tubular secretion

Biliary and Faecal Excretion

Biliary and faecal excretion

  • Any unabsorbed orally administered drugs are excreted via faeces
  • Low MW drugs (i.e. <325 in rats, <500-700 in man) are poorly excreted in bile
  • Above this MW some compounds transferred to from plasma to bile (active transport system) then GIT then faeces in appreciable amounts (vercuronium)

Enterohepatic recirculation 2

  • Bile acids are amphipathic (they have some water and some lipid solubiity) and allow absorption of fats, fat soluble vitamins etc.
  • Bile is delivered to duodenum and 95% of bile acids are reabsorbed in ileum
  • Portal vein delivers bile back to hepatocytes
  • Hepatocytes extract bile acids efficiently

Enterohepatic recirculation 1

  • β-glucuronidase from gut microflora removes glucuronide, reforming original drug that can then re-enter hepatic circulation
  • Prolongs duration of action of affected drug
  • Important for:
    • morphine
    • aspirin
    • chloramphenicol (antibiotic)
    • digoxin(inotropic agent)

Factors Affecting Excretion of Drugs

Factors affecting excretion of drugs

  • High degree of ionisation
  • High degree of water solubility
  • Non-ionised / lipid soluble substances are reabsorbed and therefore not excreted

(Opposite to those required for absorption from GIT)

Factors affecting excretion of drugs

Factors affecting excretion of drugs