General and Systematic Veterinary Pharmacology

PLASMA PROTEIN BINDING OF DRUGS

• Drugs tend to become associated with several blood constituents.
• Many drugs are bound to plasma proteins.
• It is only the unbound or free fraction of a drug that can diffuse out of capillaries into tissues.
• Factors affecting plasma protein binding include
  • Drug concentration
  • Number of drug binding sites on the protein
  • Protein concentration
  • Lipid solubility - there is a good correlation between this and the binding of penicillins and tetracyclines
  • Weak acids like penicillins are bound more extensively than weak bases
  • Competing molecules
  • Species variation
  • Disease
• Albumin and other plasma proteins are essentially contained within blood vessels and so the distribution of drugs that are bound is restricted. When more than 70 – 80 % of the drug is bound to plasma protein, it acts as a circulating reservoir for the drug.
• When two or more drugs can bind to the same site of the plasma proteins, administration of a second drug may significantly affect the binding of the first drug.
• At its therapeutic concentration warfarin is 97.4% bound. If a therapeutic dose of the non-steroidal anti-inflammatory drug phenylbutazone is administered, bound warfarin decreases to 92%. Thus free warfarin increases from 2.6 to 8%. This increases the anticoagulant effect of warfarin considerably. It also reduces its half-life from 18.4 to 9.6 hours since it is also more available for biotransformation and excretion.
• Changes in binding have the greatest effect on the proportion of free drug when the percent bound is high. Reducing the binding from 98% to 96% will double the amount of free drug from 2% to 4% and thus the half-life of the drug would be reduced much.
• The drug protein binding reaction is reversible and obeys the law of mass action.
• Drug + protein => Drug-protein complex
• Acidic drugs are bound primarily to albumin and basic drugs are bound primarily to α₁- acid glyco protein. Binding does not prevent a drug from reaching its site of action but it slows the rate at which a drug reaches a concentration sufficient to produce a pharmacologic effect.
• Drug protein binding limits glomerular filtration or an elimination process, because bound drug cannot be filtered. However, binding does not limit the elimination of drugs by active secretion or metabolized by the liver, because the fraction of the drug that is free is transported and metabolized.
• When free drug concentration is lowered, there is rapid dissociation of the drug – receptor complex to maintain the amount of drug in the free state.