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Plasma drug protein binding

Plasma drug protein binding. Update: 01:/07/2006. Biological relevance of drug binding. The binding of drug to plasma (and tissue) proteins is a major determinant of drug disposition (distribution)

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Plasma drug protein binding

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  1. Plasma drug protein binding Update: 01:/07/2006

  2. Biological relevance of drug binding • The binding of drug to plasma (and tissue) proteins is a major determinant of drug disposition (distribution) • Binding has a very important effect on drug dynamics since only the free (unbound) drug interacts with receptors

  3. Relevance of plasma and tissue protein binding • From a biological point of view  YES • From a clinical point of view  NO • problem of drug interaction and displacement has been overestimated

  4. Influence of drug binding on pharmacokinetic parameters • Distribution • Elimination o ´ ´ Q f Cl organ u int = Cl organ o + ´ Q f Cl organ u int

  5. Clinical relevance of drug binding • The importance of plasma protein binding displacement interaction has been overestimated and overstated

  6. Case for which we need to know in vivo free concentration For extrapolation • from in vitro to in vivo • in vitro, Kd (binding) and EC50 (functional response) are free concentrations but EC50 (for PK/PD) is total concentration • CMI (free) vs effective plasma concentration (Ctot) • between species • comparison of EC50 between animals requires to take into account free fraction

  7. The problem of drug interaction and displacement has been overestimated

  8. The classical example: Phenylbutazone/warfarin interaction • Interaction actually exists • Displacement actually exists • but the plasma binding displacement is not the underlying mechanism of interaction • PBZ stereoselectivity inhibits the metabolism of s-warfarin

  9. Why plasma binding seldom has clinical relevance • Because few drugs (so-called displacer) are therapeutically used • Because when displacement exists, it has no consequence on the receptor exposure to the freeconcentration of the displaced drug which generally remains unaffected

  10. Is there often displacement of drug from the binding site? • No • For a substantial displacement to take place, the displacer must occupy most of the available binding site thereby lowering the binding site available to the primary drug

  11. Is there often displacement of drug from the binding site? • No • To take place, the molar concentration of the drug in plasma must exceed the molar concentration of albumin (150 µg/mL for a a drug with a MW of 250) • e.g.: PBZ, phenytoin, valproic acid • This is not true for a1-glycoprotein acid (basic drug)

  12. Why plasma protein displacement seldom has clinical relevance • Generally only the free (unbound) drug is metabolized and can access to the receptor AND • the free drug concentration is controlled by the free drug clearance which is independent of the plasma binding

  13. Plasma drug protein bindingPhysiological aspects

  14. Plasma binding proteins Proteins MW Concentration g/L µM Albumin 67 000 35-50 500-700 -glycoprotein 42 000 0.4-1.0 9-23 acid Lipoproteins 200 000 variable to 2.4 106 Transcortin 53 000 0.03-0.07 0.6-1.4

  15. Drug binding protein concentration and percentage of free drug in serum of healthy dogs and dogs with inflammation Healthy Inflammation level of significance Total protein (g/L) 71.6 72.3 NS Albumin (g/L) 31.3 27.6 xxx a-acid glycoprotein (mg/L) 374 1632 xxx Percentage free Lidocaine 43.5 11.7 xx Propanolol 27.8 9.3 xx Phenytoin 18.1 17.6 NS Digitoxin 15.5 18.9 xx Diazepam 1.57 2.78 x Baggot The physiological basisof vet clin pharmacol p.103

  16. The free fraction & the free concentration

  17. Drug plasma protein binding • Expressed in % or by fu (free fraction) • >90% = highly bound

  18. The free fraction : fu • fu = = Definition: free concentration total concentration Cfree Ctot fu and Cfree are not synonymous terms

  19. The free, the Bound &the total concentration

  20. Cbound Bmax KD Cfree The bound concentration • The bound concentration Bmax/2 • Bmax : maximal concentration of • binding sites • proportionnal to plasma protein concentration • KD : free drug concentration corresponding to half maximal binding • inversely proportional to drug affinity for the protein

  21. Ctot is a function of Cfree Ctot = Cfree + Cbind Ctot = Cfree + Bmax x Cfree Kd + Cfree Dependent variable Parameters Independent variable controlled by Clfree

  22. Relationship between fu, the Free and the bound concentrations

  23. The free fraction fu • Physiological factors controlling fu • fu = = Cfree Cfree + Cbind Cfree Ctot

  24. The unbound fraction : fu • Linear binding : Cfree << KD

  25. Total concentration:a convenient but illicit rearrangement which can be misleading when discussing drug interaction Cfree = fu x Ctotal indirectly estimated known from in vitro assay measured by analytical technique

  26. Total concentration Ctot = • When conceptualizing dependency and functionality, this equation should not be rearranged Cfree fu !

  27. Total concentration:Why the free displaced drug concentration is not controlled by plasma binding The fundamental relationship Total concentration = independent variable free concentration fu (free fraction) parameters dependent variable Where fu is altered, Ctot is modified, not Cfree

  28. Total concentration:a convenient but illicit rearrangement which can be misleading when discussing drug interaction • What is the consequence of fu  • Ctot  = or Cfree  = fu  x Ctotal Cfree fu  NO YES Displacement (fu) modifies Ctot, not Cfree

  29. Drug interaction and protein binding

  30. AND Bmax Kd Definition Physiological relationship

  31. Drug interaction and protein binding • Ctot = Cfree + Bmax x Cfree Kd + Cfree possible interaction Interaction will modify Ctot but not Cfree

  32. Conditions in which the plasma concentration of the 2 major plasma proteins to which drug binds are altered Conditions Change in concentration Albumin hepatic cirrhosis  burns  nephritic syndrome  pregnancy  a-glycoprotein myocardial infarcts  surgery  trauma  rheumatoid arthritis  Rowland p.152

  33. Competitive interaction Ctot = Cfree + Ctot is decreased Bmax x Cfree Kd (1 + A/Ki) + Cfree Displacement

  34. Competitive interaction • Case of restrictively eliminated drug Clfree = Clint = constant Cltot = fu x Clint perfusion rate: K0 Ctot Cltot Cfree Clfree = cst redistribution Administration of the 2nd ligand, displacement  fu

  35. Competitive interaction for restrictively eliminated drugs when interaction occurs, Ctot is altered not Cfree

  36. in vitro vs. in vivo situation

  37. In vitro - closed system In vivo - open system Drug with low extraction ratio Css, tot = constant Css, free perfusion rate constant = = Cl Css, free = f C 1 int Css, tot u ss, tot Css, free = fu if fu then Ctot if fu then Cfree Effect 1.0 1.0 Ctot fu = 0.4 0.5 Ctot fu = 0.2 0.5 fu = 0.2 Cfree fu = 0.4 0.2 0.2 Cfree Time Time Competitive interaction Competitive interaction

  38. fu vs Cfree: in vitro situation 4 4 2 1 fu = 0.5 Cfree = 3/V Ctot = 6/V 2 1 5 5 3 3 6 6 fu = 0.83  Cfree = 5/V  Ctot = 6/V  displacer displacee V= volume of the baker

  39. fu vs Cfreein vivo situation: initial steady state Extracellular fluid Intracellular fluid Plasma 4 1 2 Infusion=A A=MT-1 K12 Cfree 5 3 6 K21 Cfree Elimination = K10 x Cfree (3) = A equated by infusion TOTAL CONCENTRATION = 6/V FREE CONCENTRATION = 3/V

  40. Just displaced free drug fu vs Cfree: in vivo situation:just after administration of displacer displacer Extracellular fluid Intracellular fluid Plasma K12xCfree: increase transitively 1 4 2 Infusion=A A=MT-1 5 3 6 K21 x Cfree TOTAL CONCENTRATION = 6/V  FREE CONCENTRATION = 5/V  Increase transitorily K10 x Cfree (5) > A

  41. fu vs Cfree: in vivo situation: final steady state displacer Extracellular fluid Intracellular fluid Plasma K12 x Cfree 1 2 Infusion=A A=MT-1 3 6 K21 x Cfree TOTAL CONCENTRATION = 4/V  FREE CONCENTRATION = 3/V  Elimination = K10 x Cfree (3) = A

  42. The three main exceptions to the general rule for which drug interaction has no clinical meaning 1. Rapid bolus IV injection 2. Parenteral administration of displaced drug with a high extraction ratio 3. Therapeutic drug monitoring and drug displacement from the plasma binding site

  43. Case for which drug interaction at the binding site is relevant 1. Rapid IV injection • If the displacing agent is given rapidly (IV bolus), the Cfree could increase dramatically due to rapid displacement of the displaced drug before the compensatory mechanism (redistribution) takes place • Sulfamide and bilirubin  kernicterus

  44. Case for which drug interaction at the plasma binding site is relevant 3. Therapeutic drug monitoring and drug displacement from plasma binding • Therapeutic drug monitoring is performed for drugs with a narrow concentration range between therapeutic and toxic effect • Monitoring is carried out on total plasma concentrations

  45. Case for which drug interaction at the plasma binding site is relevant 3. Therapeutic drug monitoring and drug displacement from plasma binding • An example: • Phenytoin alone: Ctot = 20 µg/mL • Phenytoin + Valproic acid: Ctot = 15 µg/mL • no dosage adjustment is necessary because Ctot decreased but not Cfree due to fu increase

  46. Algorithm for determining clinical significance of potential binding displacement interaction Roslan 1994, B.J.Clin Pharmacol. 37, 125 Is drug of interest >90% protein bound? no Clinically significant interaction not likely Yes no Does the drug have a narrow therapeutic index ? no Yes low Would a transient increase in free drug concentration be clinically relevant ? What is the hepatic extraction ratio of the drug ? High Yes no Is the drug given IV? Clinically significant interaction likely. Perform a clinical study to quantify effects Yes

  47. Protein Binding Interactions “…the overall clinical importance of plasma protein binding displacement interactions continues to be overstated…” “Despite the theoretical and experimental data to the contrary, the concept that plasma protein binding displacement is a common cause of clinically significant interactions may still be widely taught in some medical schools, often appears in textbooks and is accepted by many in the medical community and by drug regulators.” Sansom LN & Evans AM. Drug Safety 1995;12:227-233. Rolan PE. Br J Clin Pharmacol 1994;37:125-128.

  48. Protein Binding Interactions • Drugs for which pure plasma protein binding displacement interactions will lead to sustained changes in Cssu • Extensively bound to plasma proteins • Nonrestrictively cleared • Administered by non-oral route • alfentanil, buprenorphine, lidocaine, verapamil • Very few orally administered drugs exhibiting properties of extensive plasma protein binding, high hepatic first-pass extraction and narrow therapeutic index

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