Protein binding plays an important role in drug distribution, activity, and excretion. It can facilitate drug distribution through the body, inactivate drugs by preventing sufficient free concentrations from reaching receptor sites, and retard drug excretion. The main plasma proteins that drugs bind to are albumin and alpha-1-acid glycoprotein. Albumin is the most abundant and binds both acidic and basic drugs. Alpha-1-acid glycoprotein binds mainly to basic drugs. Only the unbound, free fraction of a drug is biologically active and able to diffuse to tissue sites to exert its therapeutic effects. Protein binding is determined by various analytical techniques and is important pharmacokinetically as it influences drug distribution throughout the body.

1. PROTEIN BINDING
Bindingof drug to proteinsmay:
 Facilitate the distributionof drugs
 Inactivate the drugby notenablingasufficientconcentrationof free drugtodevelopata
receptorsite
 Retardthe excretionof adrug
The interactionof drugs to protein may cause:
 Displacementof bodyhormonesorcoadministeredagent
 Change the configurationof proteintoanotherstructure capable of bindingacoadministered
agent
 Inactivatesthe drugbiologicallybyformingadrug-proteincomplex
Structure of BindingSite ofColon-CancerDrug and Its
Two Important Plasma Proteins
ALBUMIN
 Is the mostimportantproteinthatbindsto drugmolecule due toitshighconcentration
comparedwithotherproteins
 It bindsbothacidicand basic
 Constitute 5%of the total plasma

2. ∂1-ACIDGLYCOPROTEIN
 Alsoknownasorosomucoid(∂1-globulin)
 Bindsto numerousdrugs
 Have greateraffinityforbasicthanacidic drugsmolecules
 Bindsonlybasicand highlylipophilicdrugs
Things to remember:
 Many drugs bindto the same receptor site butdrugswithhigheraffinitywill replace those drugs
withloweraffinitybycompetition
 Onlyfree andunbounddrugsexerttherapeuticeffectbyinteractingwithreceptors
Drugs may bindto proteinthrough:
Hydrophobic Interaction
 ProposedbyKauzmann
 tendencytodevelopof hydrophobicmoleculesorpartsof moleculestoavoidwaterbecause
theyare notreadilyaccommodatedinthe H-bondstructure of water
Bindingof Ca to a target protein

3. Drugs may bindto proteinthrough:
Self-Association
 Some drug mayself dissociate toformdimers,trimersoraggregatesof largersize
 Dimersor trimers - is a reactionproductof twoor three identical molecules
 May affectsolubility,diffusion,transport,therapeuticactionof drugs
Proteinbindingis determinedby:
 Dialysis
 Ultracentrifugation
 Ultrafiltration
 Sephadex-gelfiltration
 Molecularfiltration
 Electrophoresis
 Agar plate test
The PharmacokineticImportance of ProteinBinding
 Drug-proteinbindinginfluencesthe distributionequilibriumof the drug
 Plasmaproteinsexertabufferandtransportfunctioninthe distributionprocess
 Onlyfree andunbounddrugacts can leave the circulatorysystemanddiffuse intothe tissue
Disease and ProteinBinding
 Whendrugs bindtoprotein,Albuminconcentrationisreduced

4.  The exchange of proteinsbetweenplasmaandinterstitial compartment(normally proceedsata
rate of 5% plasma protein per our) will be hampered.
 The diffusionof plasmathe tointerstitial fluidisincreasedby:
1. Inflammatoryprocess
2. Pregnancy
3. use of oral contraceptives
4. Diabetes
5. Septicshock
6. PulmonaryEdema
Disease and ProteinBinding
 The reducedalbuminconcentrationandbindingcapacityisdue to:
 Change inalbuminmolecule
 presence of endogenousbindinginhibitorssuchas free fatty acids,andmetabolicacidosis.
 Hypoalbuminemiamayresultinpatientswithcancer,burms,cardiacfailure,cysticfibrosis,
enteropathy,inflammations,liverimpairment,malabsorption,nephroticsyndrome,renal
failure,sepsisandtrauma.
Bindingof Drugs to RBC
 Lipophilicmoleculesdissolvedinthe lipidmaterial of the RBCmembrane
 Anionscanbe attractedto and enterthe positivelychargedporesof RBC
 Lipopilicdrugsmaybe absorbedtorBC membrane due tochange of:
1. Change of shape of membrane andmembrane proteins
2. Membrane extensionwhichmayleadtochane of RBC shape
 Drugs absorbedinthe RBC membrane inhibitsthe deformityof RBCthusbecominglodgedinthe
capillaries
 Macrophagesmay remove the RBC,that resultsinincrease free drugconcentration
 Bindingof drugsto RBC may be dependentonage (meperidine) andconcentrationdependent
(diazepam)
The RBC bindingsitesare:
 Intracellularproteins
 Hemoglobin
 Carbonicanhydrase
 Cell membrane
 ATPase
Beneficial effectsoftissue binding:
 Lowertissue uptake
 Lesserretentionincritical organsuchas kidney,etc.

5. Displacementofdrugs from ProteinBindingis due to:
 Total amountof protein-bounddruginthatbody
 Extentof tissue bindingstructure
 Apparentvolume of distribution