PKPD

• Modes of drug transport across a membrane


  1. Drug in blood/plasma

  2. Passive transcellular diffusion

  3. Passive diffusion

  4. Paracellular saturable, limited

  5. Passive facilitated transcellular diffusion

  6. Active transport

  7. Equilibrating carrier-mediated

  8. Concentrating transporters

  9. Directional-influx

  10. Efflux

  11. ATP-dependent, against concentration gradient
• Protein binding


  Unbound = fu, Bound = 1-fu
• Transporters affect the number of proteins unbound
• Efflux transporters like MDR1/PGP mediate drug transport
• Factors affecting drug movement across membrane

  • Physicochemical properties of drug
  • Membrane characteristics
  • Exposure-time profiles
• Physicochemical properties


  Size, permeability, charge, solubility, polarity, lipophilicity, acidic/basic, molecular weight
• Membrane characteristics


  Porosity, fenestrated, sinusoid, thickness
• Exposure-time profiles


  Plasma drug concentration vs time

  
• Plasma is cleaner than blood for PK analysis
• Physicochemical properties may not be the only factors affecting drug movement across membranes
• Blood-brain barrier


  Very tight junctions, many efflux transporters (MDR1/PGP)
• Oral systemic bioavailability, F


  F = FF x Fg x FH
• PK models


  1. Compartment models

  2. Group of tissues with similar blood flow & drug affinity

  
• Apparent volume of distribution, V


  Drug binds to body water but also plasma/tissue/fat/bone, lower than expected [drug] means larger than expected V

  
• First-order kinetics (IV bolus)


  Body burden decreases, elimination rate decreases, most drugs have first-order elimination
• Elimination rate constant, k


  Units: time^-1, Higher concentration means higher gradient and higher elimination rate
• ADME


  Absorption, Distribution, Metabolism, Excretion
• Clearance, CL


  Volume of blood/plasma cleared of drug per unit time, CL = Rate of Elimination / Concentration
• Extraction ratio, E


  Fraction of drug removed from blood/plasma as it crosses the eliminating organ
• Hepatic clearance, CLH


  CLH = CLint,m + CLint,b (metabolism + biliary elimination)
• Renal clearance, CLR


  CLR = (1-FR) x [CLf + CLs] (filtration + secretion)
• Renal extraction ratio, ER


  ER = GFR x fu / QR
• Free drug fraction, fu


  Only the free/unbound drug is active, distributed, metabolised, excreted, interacts with receptors/enzymes
• Intestinal mucosa and liver have CYP enzymes that can metabolise drugs
• Examples of drugs


  • NSAIDs
  • coumarin anticoagulants
  • anticonvulsants
• If CLRC GFRXfu, CLR > CLE


  Can infer that active secretion takes place due to high affinity for plasma albumin and low affinity for tissue protein
• Renal Extraction Ratio (ER)


  Types of plasma proteins
• Assumptions: normal rate of glomerular filtration (QR = 1.1 L/min)
• Types of plasma proteins


  • Albumin
  • α1-Acid Glycoprotein (α1-AGP)
  • Lipoproteins
  • Transcortin
• Albumin


  Most abundant plasma protein
• Drug selectivity


  • Wide for drugs totally unbound in blood (Cu, b = 1)
  • Lipophilic amines (basic) for α1-AGP
  • Lipophilic drugs for lipoproteins
  • Corticosteroids for Transcortin
• Extraction ratio (E) of drug by filtration alone is low (even lower if high free drug fraction, fu)
• Free drug fraction (fu)


  Only the free/unbound drug is active at active site, distributed into tissues, metabolised, excreted, interact with receptors/enzymes
• Drug disposition


  1. Phase I reactions: Oxidation, reduction, hydrolysis

  2. Phase II reactions: Conjugation with polar endogenous compounds to make it more water soluble (e.g. UDPG)
• fu and fut are independent of each other, cannot use fu and fut to predict whether drug tissue concentration between fu and fut
• Routes of drug elimination


  • Kidneys (glomerular filtration, tubular secretion)
  • Biliary tract in liver (High MW drugs, conjugate metabolites)
  • Lungs for volatile agents (anaesthetics)
• Some drugs have high ER due to tubular secretion
• Pharmacokinetic Parameters following IV bolus administration


  1. C = C0.e-kt

  2. Inc = -kt + Inc0

  3. k = (Inc1 - Inc2)/(t2 - t1)

  4. t1/2 = 0.693/k

  5. V = Dose/C0

  6. AUC0-∞ = Dose/CL
• Pharmacokinetic Parameters


  • Primary PK Parameters: F, CLH, Vp

  Secondary PK Parameters: t1/2, k

  Observations: AUC, Cmax
• Pharmacokinetic parameters are affected by physiological variables such as disease