DRUG PROTEIN BINDING

PROTEIN BINDINGOF DRUGS : 

PROTEIN BINDINGOF DRUGS BY N.RAJU M.PHARMACY-I SEMESTER DEPARTMENT OF PHARMACEUTICS BALAJI INSTITUTE OF PHARMACEUTICAL SCIENCES LAKNEPALLY

CONTENTS : 

CONTENTS INTRODUCTION CONSIDERATIONS OF THE STUDY DRUG PROTEIN BINDING BINDING OF DRUGS TO BLOOD COMPONETNTS EFFEC T OF PROTEIN BINDING ON APPARENT VOLUME OF DISTRIBUTION FACTORS AFFECTING OF PROTEIN BINDING KINETICS OF PROTEIN-DRUG BINDING SIGNIFICANCE OF PROTEIN BINDING

INTRODUCTION : 

INTRODUCTION Bound Drug is Pharmaodynamicaly inert. Binding: Half life of drug. Bonding : Hydrogen bond, Hydrophilic bond, ionic bond, Vander Walls bond. Irreversible bonding : Covalent bonding : responsible for the Carcinogenicity or Tissue toxicity. 3

BINDING OF DRUG : 

BINDING OF DRUG

BINDING OF DRUGS TO HUMAN SERUM ALBUMIN : 

BINDING OF DRUGS TO HUMAN SERUM ALBUMIN Albumin m.wt 65,000 – 69,000 It is synthesized in the liver . It is major component of plasma proteins. Responsible for reversible drug binding . Albumin is distributed in the plasma and in the extracellular fluids of skin , muscle ,and various tissues. Intestinal fluid albumin concentration is about 60% of that in the plasma .

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The elimination half life of albumin is 17-18 days . Albumin concentration is 3.5-5.5%(weight per volume) or 4.5 mg/dl. Albumin is responsible for maintaining the the osmatic pressure of the blood and for the transport of endogenous and exogenous substances.

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As a transport protein for endogenous substance ,albumin complexes with Free fatty acids , Billirubin and various hormnes (such as cortisone , aldosterone ,and thyroxine) Tryptophan . Many weak acidic drugs bind to albumin by electrostatic and hydrophobic bonds.

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Weak acidic drugs such as Sallicylates,phenylbutazone ,and penicillins are highly bound to albumin.

Major proteins to which drugs bind in plasma : 

Major proteins to which drugs bind in plasma I

BINDING OF α-1 ACID GLYCOPROTEINS : 

BINDING OF α-1 ACID GLYCOPROTEINS It is also called as the orosomucoid ,it has m.wt 44,000. Binding by: Hydrophobic bonds E.g. : Basic Drugs: Imipramine, Amytriptyline, Lidocaine, Nortriptyline Propranolol, Quinidine and disopyramide

BINDING OF DRUGS TO GLOBULINS : 

BINDING OF DRUGS TO GLOBULINS

BINDING OF DRUGS TO LIPOPROTEINS : 

BINDING OF DRUGS TO LIPOPROTEINS Binding by hydrophobic bond,non competitive M.wt ; 2-3 lakhs to 34 lakhs Binded drug dissolve in lipid core Lipid core composed of Inside ;triglycerides,cholesterol esters Outside;apoprotein eg.;acidic ;diclophenac Neutral;cyclosporin-a Basic;chlorpromazine

BINDING OF DRUGS TO BLOOD CELLS : 

BINDING OF DRUGS TO BLOOD CELLS 40 % of Blood comprises of blood cells Majority is RBCs: 500 times more diameter as Albumin. RBC Components that binds to drug:

EFFCET OF PROTEIN BINDING ON THE APPARENT VOLUME OF DITRIBUTION : 

EFFCET OF PROTEIN BINDING ON THE APPARENT VOLUME OF DITRIBUTION The extent of drug protein binding in the plasma or tissue affects Vd. Drugs that are highly bound to plasma proteins have low concentration of free drug in the plasma water. The plasma protein –bound drug does not diffuse easily and is therefore less extensively distributed to tisses. Drugs with low plasma protein binding have larger fu(unbound or free drug fraction),generally diffuse more easily into tissues ,and have greater volume of distributions .

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Since the apparent volume of distribution is influenced by lipid solubitlity in addition to protein binding ,there are some exceptions to this rule.

FACTORS AFFECTINNG PROTEIN -DRUG BINDING : 

FACTORS AFFECTINNG PROTEIN -DRUG BINDING 1)THE DRUG Physicochemical properties of the drug lipophilicity protein binding. cloxicillin is higher lipophilicity which is 95% bound amoxicillin which is less lipophilic , just 20% bound to proteins DRUG PROTEIN –TISSUE AFFINITY Lidocaine has greater affinity for AAG then HSA Digitoxin has more affinity for cardiac muscle than those of skeletal muscle. Iophenoxic acid ,radiopaque medium has greater affinity to plasma proteins

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2)DRUG INTERACTIONS Competion for the drug by other substances at a protein-binding site When 2 drugs or more can bind to same site ,competition between them for interaction with the binding site results. Drug A binds to plasma protein,then adminster another drug (drug B) having affinity for the same site results in displacement of drug A from its site.

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Such a drug -drug interaction for combined site is called as displacement interaction. Warfarin and phenylbutazone have same affintiy for HSA Administered phenylbutazone to a patient to warfarin therapy results in displacement of latter from its binding site . The free warfarin causes adverse hemorrhagic reactions which may be fatal.

NUMBER OF BINDING SITES : 

NUMBER OF BINDING SITES Alb. Has more. TamoxifeAn & Dicumarol binds to 10 & 20 sites of alb. Indomethacine binds to 3 site

COMPETION BETWEEN DRUG AND NORMAL BODY CONSTITUENTS : 

COMPETION BETWEEN DRUG AND NORMAL BODY CONSTITUENTS FFA competes with HSA. Free FFA level increased during conditions : Physiological C. (Fasting) Pathological C. (Diabetes, M.I) Pharmacological (Heparin & Caffeine adm.). Acidic Drug displaces : Bilurubine from Alb. & results in Kernictarus.

PATIENT RELATED FACTORS : 

PATIENT RELATED FACTORS AGE Neonates: Low Alb. content: more free drug. Young Infants: High dose of Digoxine due to large renal clearance. Elderly: Low Alb. : so more free drug.

DISEASE STATES : 

DISEASE STATES

KINETICS OF PROTEIN BINDING : 

KINETICS OF PROTEIN BINDING P =protein, d=drug, then applying law of mass action to reversible protein drug binding p+d <=> pd (pd) ka = (p)(d) pd =ka(p)(d) P=concentration of protein Pd=concentration protein drug complex Ka=association constant Kd=dissociation constant

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Ka>>kd indicates forward reaction i.e protein drug binding is favoured . Pt =total conc.of protein ,bound and unbound Pt =(pd) + (p) then r = total number of moles drug that bound to protein r = (pd)/(pt) = (pd)/(pd)+(p) Substuting the value of (pd)from the 2- equation r = ka(p)(d)/ka(p)(d)+(p) = ka(d)/ka(d)+1 The above equation holds when there is only one binding site on the on the protein and protein –drug complex ratio 1:1 If more then one or N number of binding sites are avalible per mole of the protein then r = n ka(d)/ka (d)+1

SIGNIFICANCE OF PROTEIN BINDING OF DRUGS : 

SIGNIFICANCE OF PROTEIN BINDING OF DRUGS ABSORPTON SYSTEMIC SOLUBILITY OF DRUGS DISTRIBUTION ELIMINATION KERNICTERUS THERAPY AND DRUG TARGETING

ABSORPTION : 

ABSORPTION The absorption equilibrium is attained by transfer of free drug from the site of administration into the systemic circulation and when the concentration in these two compartments become equal. However ,binding of the absorbed drug to plasma proteins decreases free drug concentration and disturbs such an equilibrium .

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Thus , sink conditions and the concentration gradient are reestablished which now act as the driving force for further absorption. This is particularly useful incase of ionized drugs which are transported with difficulty.

SYSTEMIC SOLUBILITY OF DRUGS : 

SYSTEMIC SOLUBILITY OF DRUGS Water insoluble drugs ,neutral endogenous macromolecules such as Heparin , Oil soluble vitamins are circulated and distributed to tissues by binding especially to lipoproteins which act as a vehicle for such hydrophobic compounds.

DISTRIBUTION : 

DISTRIBUTION Plasma protein binding restricts the entry of drugs that have specific affinity for certain tissues . This prevents accumulation of large fraction of drugs in such tissues and thus,subsqent toxic reactions. plasma protein binding thus favors uniform distribution of drugs throughout the body by its buffer function A protein bound drug in particular does not cross the BBB ,the placental barrier and the glomerulus.

ELIMINATION : 

ELIMINATION Only the unbound drug is capable of being eliminated. This is because the drug protein complex cannot penetrate into the liver . The large molecular size of the complex also prevents it from getting filtered through the glomerulus . Thus, drugs which are more than 95% bound are eliminated slowely i.e they have long eliminaton half lives ;for eg tertacycline ,which is only 65% bound ,has an elimination half life of 8.5 hours in comparision to 15.1 hours of doxycycline which is 93% bound to plasma proteins .

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However penicillines have short have –lives despite being extensievely bound to plasma proteins . This is because rapid equilibration occurs between the free and the bound drug and the free drug is equally rapidly excreated by active secretion in renal tubules.

THERAPY AND DRUG TARGETING : 

THERAPY AND DRUG TARGETING The binding of drugs to lipoproteins can be used for site specific delivery of hydrophilic moieties. This is particularly useful in certain cancer therapys because certain tumor cells have greater affinity to for LDL then normal cells. Thus binding a suitable antineoplastic to it can be used as therapetic tool. Estradiol binds selectively and strongly to prostrate and thus prostate cancer can be treated by attaching nitrogen mustered to estradiol for targeting of prostate glands.

CONCLUSION : 

CONCLUSION All pharmacokintic parameters can be influenced by protein binding. Bound drug cannot penetrate through blood capilaries , so that the bound drug pharmacologically inert. Plasma –protein bound drug have longer elimination half lives compare to the free drug.

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Protein bound drug doesn’t cross BBB and placental barrier . Estradiol binds selectively and strongly to prostate and thus prostate cancer treated by attching nitrogen mustard to estradiol for targeting of prostate glands.

Reference : 

Reference Leon shargel Gibaldi Scince direct Wisegeek Answers .com Pub med

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