Drug Related Factors

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Chapter: Biopharmaceutics and Pharmacokinetics : Protein Binding of Drugs

Drug Related Factors: Physicochemical Characteristics of the Drug, Concentration of Drug in the Body, Drug-Protein/Tissue Affinity


Physicochemical Characteristics of the Drug

As mentioned earlier, protein binding is directly related to the lipophilicity of drug. An increase in lipophilicity increases the extent of binding, for example, the slow absorption of cloxacillin in comparison to ampicillin after i.m. injection is attributed to its higher lipophilicity and larger (95%) binding to proteins while the latter is less lipophilic and just 20% bound to proteins. Highly lipophilic drugs such as thiopental tend to localize in adipose tissues. Anionic or acidic drugs such as penicillins and sulphonamides bind more to HSA whereas cationic or basic drugs such as imipramine and alprenolol bind to AAG. Neutral, unionised drugs bind more to lipoproteins.

Stereoselectivity in protein binding of enantiomeric drugs has also been demonstrated. Acidic drugs such as etodolac, flurbiprofen, ibuprofen, moxalactam, pentobarbital, phenprocoumon, and warfarin and for basic drugs such as chloroquine, disopyramide, methadone, propranolol, mexiletine, and verapamil show stereoselective binding.

Concentration of Drug in the Body

The extent of protein-drug binding can change with both changes in drug as well as protein concentration. The concentration of drugs that bind to HSA does not have much of an influence, as the therapeutic concentration of any drug is insufficient to saturate it. However, therapeutic concentration of lidocaine can saturate AAG with which it binds as the concentration of AAG is much less in comparison to that of HSA in blood.

Drug-Protein/Tissue Affinity

Lidocaine has greater affinity for AAG than for HSA. Digoxin has more affinity for proteins of cardiac muscles than those of skeletal muscles or plasma. Iophenoxic acid, a radio-opaque medium, has so great an affinity for plasma proteins that it has a half-life of 2½ years.

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