Question

Describe the clinical significance of protein binding interactions citing the situations in which such interaction becomes clinically important .

Answer 1

The significance of plasma protein binding on drug efficacy and, subsequently, the clinical relevance of changes in protein binding has been controversially discussed for decades. The uncertainty concerning the impact of plasma protein binding on a drug's pharmacological activity is, in part, related to the approach used when investigating and interpreting protein binding effects in vitro and in vivo. Frequently, a generalized one-size-fits-all approach, such as "protein binding does matter/does not matter," may not be applicable. An appropriate analysis requires careful consideration of both pharmacokinetic and pharmacodynamic processes, as they both contribute to the safety and efficacy of drugs. Therefore, the aim of this article is to provide a concise review of the theoretical concepts of protein binding, and to discuss relevant examples where applicable.

Binding of drug to human serum Albumin.
• It is the most abundant plasma protein (59%), having M.W. of
65,000 with large drug binding capacity.
• Both endogenous compounds such as fatty acid, bilirubin as well
as drug binds to HSA.
• Four diff. sites on HSA for drug binding.
Site I: warfarin & azapropazone binding site.
Site II: diazepam binding site.
Site III: digitoxin binding site.
Site IV: tamoxifen binding site.

BINDING OF DRUG TO BLOOD CELLS
•
•
In blood 40% of blood cells of which major component is RBC
(95%). The RBC is 500 times in diameter as the albumin. The
rate & extent of entry into RBC is more for lipophilic drugs.
The RBC comprises of 3 components.
a) Haemoglobin: It has a M.W. of 64,500 Dal. Drugs like
phenytoin, pentobarbital bind to haemoglobin.
b) Carbonic anhydrase: Carbonic anhydrase inhibitors drugs are
bind to it like acetazolamide & chlorthalidone.
c) Cell membrane: Imipramine & chlorpromazine are reported to
bind with the RBC membrane.