IC10

• Elimination processes


  1. Metabolism/Biotransformation

  2. Excretion
• Metabolism/Biotransformation


  Conversion of the parent drug to metabolite, usually rendering it inactive and make the drug more polar for excretion
• PHASE I of metabolism/biotransformation


  • oxidation
  • reduction
  • hydrolysis
• PHASE II of metabolism/biotransformation


  • conjugation with polar endogenous compounds, rendering it more water-soluble
• Sites of metabolism/biotransformation


  • Intestinal mucosa
  • Liver
• Fate of drug


  • Metabolites can be pharmacologically active
  • PK-PD is now more complex
• Sites of excretion


  • Kidneys: glomerular filtration, tubular secretion
  • Biliary tract (liver): high MW drugs, conjugate metabolites
  • Lungs: volatile agents (e.g. anesthetics)
• Excretion


  Irreversible loss of chemically unchanged drug/parent drug
• Clearance


  Volume of blood/plasma cleared of drug per unit time
• Clearance


  That of a drug is the proportionality factor that predicts the rate of elimination in relation to the drug concentration
• Extraction ratio (E)


  The fraction of drug that is removed from the blood or plasma as it crosses the eliminating organ
• Extraction ratio limits: 0<E<1 (no what comes in goes out no extras)
• High extraction ratio (E very high)


  Output concentration is very low, organ blood clearance becomes limited by blood flow (flow/perfusion limited CL)
• Low extraction ratio (E very small)


  Drug is not efficiently extracted by the organ, organ blood clearance is only a small fraction of blood flow (Q) and it is largely independent of blood flow (capacity-limited CL)
• Intrinsic hepatic clearance


  Pathways: Metabolizing by hepatocytes or excreted into the bile
• Factors affecting hepatic clearance (CLH)

  • Perfusion
  • Binding to blood cells
  • Binding to plasma proteins (fraction unbound drug, FU)
  • Permeation or transport of unbound drug into hepatocytes (C)
  • Elimination via secretion into bile (biliary clearance)
  • Elimination via metabolism (intrinsic metabolic clearance)
• External factors affecting hepatic clearance


  • Disease
  • Genetic polymorphism
  • Age
• High extraction ratio drugs (Eh>0.7)


  High efficiency in partitioning out of blood cells, dissociation from plasma proteins, permeation through hepatic membranes, metabolism by hepatic enzymes, biliary extraction into bile. Organ blood clearance becomes flow/perfusion limited CL. Clearance is sensitive to changes in Qh but relatively insensitive to changes in plasma protein binding or hepatocellular eliminating activity.
• Low extraction ratio drugs (Eh<0.3)


  Common reasons for poor efficiency: drug is a poor substrate for the elimination process, is polar and has insufficient lipophilicity to permeate readily into hepatocytes, is substrate of efflux transporter along to sinusoidal (basolateral) membrane. Clearance is insensitive to changes in Qh but relatively sensitive to changes in plasma protein binding or hepatocellular eliminating activity.
• Renal clearance


  FR= fraction reabsorbed
• Contributions to renal clearance

  • Glomerular filtration
  • Tubular secretion
  • Tubular reabsorption
• Primary PK parameters


  • Bioavailability (F)
  • Apparent volume of distribution (V)
  • Total CL (Hepatic clearance, Renal clearance)
• Secondary PK parameters


  • Elimination half-life
  • Elimination rate constant
  • AUC
  • CLMAX
• Primary PK parameters are independent of each other and may be directly affected by changes in physiologic variables like age, disease etc. Secondary PK parameters depend on the values of primary PK parameters.
• Volume of distribution (V)


  Related to physicochemical properties of drug, plasma protein and tissue protein binding
• Clearance (CL)


  Related to capacity and ability of clearing organs to remove drug
• 1. renal and biliary excretion often involve drug transporters that can concentrate drug in urine and bile respectively
• Major sites of excretion of unchanged parent drug

  1. Kidneys: glomerular filtration, tubular secretion
  2. biliary tract in the liver: high MW drugs, conjugate metabolites
  3. lungs for volatile agents: anesthetics