The protein pocket performs magically in controlling, inhibiting, or optimizing various biochemical processes. The elegant 3D disposition of different side chains in the cavity is a key point in accommodating specific ligands. Anion receptors in the subdomain-IIA pocket of serum albumin (SA) prefer to home anionic ligands. Acid-base behavior is an important property that relates to bioavailability and action of prototropic molecules/drugs. The present study provides a comprehensive understanding of the effect of subdomain-IIA pocket-specific interaction on the acid-base equilibrium of housed guests. The pK(a) of subdomain-IIA binder basic drugs decreases due to unfavorable interaction with the cationic drug species, while the decrease in the pK(a) of acidic drugs is due to favored binding of the deprotonated species presumably via electrostatic interaction with anion receptors. Acidity-shifting efficacy of albumins is introduced for the first time using the pK(a)-shifting index (alpha), a unique parameter for a given prototropic-drug-host pair to assess bioavailability. The acidic drug warfarin and the basic drug fuberidazole, showing a high alpha-value, should be efficient in drug-SA cocktail, and those with low a should be less efficient. Use of the pK(a)-shifting index for prototropy-based drugs should enable the drug efficacy to be evaluated smartly for similar systems. Shifting of the pK(a) of protein-encapsulated drugs stems the possibility of albumin-based delivery systems for extracting the therapeutically active species.