Drug intreaction

Topic: drug interaction
Advanced biopharmaceutics and pharmacokinetics

1. DRUG INTREACTION: THE EFFECT OF PROTEIN BINDING INTREACTION, THE EFFECT OF TISSUE-BINDING INTREACTION, CYTOCHROME P450-BASED DRUG INTREACTION, DRUG INTREACTION LINKED TO TRANSPORTER . PREPARED BY - MANSI GANGWAR ENROLLMENT NUMBER- 202130820004 BRANCH- PHARMACEUTICS M.PHARM 2ndSEM SUBJECT- ADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS (MPH202T) 1

2. CONTENT Effect of protein binding interaction Effect of tissue binding interaction Cytochrome p450-based drug interaction Transporter based drug intreaction 2

3. INTRODUCTION Drug–drug interactions (DDIs)  occur when one drug interferes with the pharmacological activity of another . Drug interactions can take place at many different sites in the body - notably in the gastrointestinal tract, at plasma protein and tissue binding sites, in the liver, and in the kidney These interactions can result in decreased effectiveness and/or increased toxicity. Additionally they may result in the development of ADRs, morbidity, hospitalizations and sometimes death. 3

4. The interacting molecules are generally the macromolecules such as protein, DNA or adipose. The protein are particularly responsible for such an interaction. The phenomenon of complex formation of drug with protein is called as protein binding of drug. As a protein bound drug is neither metabolized nor excreted hence it is pharmacologically inactive due to its pharmacokinetic and Pharmacodynamic inertness. Protein + drug ⇌ Protein-drug complex 4 ＋=+ =+ PROTEIN-DRUG BINDING INTREACTION PROTEIN DRUG BINDING

5. Binding of drugs to proteins is generally of reversible & irreversible. Reversiblegenerally involves weak chemical bond such as: 1 . Hydrogen bonds 2. Hydrophobic bonds 3. Ionic bonds 4. Van der Waal's forces Irreversible drug binding , is usually a result of chemical activation of the drug, which then attaches strongly to the protein or macromolecule by covalent chemical bonding and is often a reason for the carcinogenicity or tissue toxicity of the drug 5 MECHANISM OF PROTEIN DRUG BINDING

6. BINDING OF DRUG TO VARIOUS COMPONENT OF BODY 6

7. A) BINDING OF DRUGS TO BLOOD COMPONENTS 1 ) Plasma Protein-drug Binding The binding of drugs to plasma proteins is reversible. The extent or order of binding of drug to plasma proteins is: Albumin › ὰ1-Acid glycoprotein › Lipoproteins › Globulins 7

8. a ) 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. Endogenous compounds & Large variety of all types of drugs 8

9. b ) Binding of drug to ὰ 1- Acid glycoprotein: ( orosomucoid ) It has a M.W. 44,000 and plasma conc. range of 0.04 to 0.1 g%. It binds to no. of basic drugs like imipramine, lidocaine , propranolol, quinidine 9

10. c ) Binding of drug to Lipoproteins : Lipoproteins can also bind to such drugs because of their high lipid content. A drug that binds to lipoproteins does so by dissolving in the lipid core of the protein and thus its capacity to bind depends on the lipid content Mol wt : 2-34 lakhs Classified as : LDL ,HDL , VLDL, Chylomicrons Binding is non – competitive and does not depend on drug concentration Lipophilic basic > acid and neutral Transport of drug to tissues 10

11. d) Binding of drug to globulins It mainly binds to endogenous substances. In plasma several globulins have been identified. ἀ1- globulin :- ( transcortin ) corticosteroid binding globulin. ἀ2- globulin :- ( ceruloplasmin ) it binds vita. A, D, E, K & cupric ions. ᵝ1-globulin :- (transferrin) it binds to ferrous ions. 11

12. 2) 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. Thus , significant RBC-drug binding is possible.The RBC comprises of 3 components: a ) Hemoglobin: 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 membraneImipramine: Imipramine & chlorpromazine are reported to bind with the RBC membrane & chlorpromazine are reported to bind with the RBC membrane. 12

13. B) BINDING OF DRUGS TO EXTRAVASCULAR TISSUES:- The tissue-drug binding is much more significant because the body tissues comprise 40% of the body wt which is 100 times that of H SA . A tissue can act as the storage site for drugs. Factors that influence localization of drug in tissues are lipophilicity & structural features of the drug, perfusion rate, pH differences etc. Liver › Kidney › Lung › Muscles Several example of extravascular tissue-drug binding are: Liver, Lungs, Kidneys, skin, eyes, hairs, etc. It also seen in hairs, bones, fats & nucleic acids, etc 13

14. Effect of Protein Binding on Drug Kinetics PLASMA PROTEIN BINDING Absorption : The absorption process is considered to be favoured if a drug is highly bound, as a large concentration gradient is maintained between free drug at the absorption site and free drug in the plasma Distribution This is decreased if a drug is highly bound to plasma proteins, as bound drug is not available for diffusion into the tissues . This means that extensively plasma bound drugs tend to have a low apparent volume of distribution ( Vd ). Warfarin , for example, is highly bound to plasma albumin and has a V d of 0.1 L/kg, indicating poor diffusion into the tissues 14

15. Metabolism : Binding of drugs to plasma protein may also affect their metabolism. This , however, will depend on whether or not active processes are involved in the metabolic activity. If a drug has a high extraction ratio (i.e. is highly cleared during its passage through the metabolising organ), metabolism will often involve active uptake of the drug into, for example, liver cells Drugs with a low extraction ratio will depend more on passive uptake mechanisms When active mechanisms are involved, affinity for metabolising fractions will normally exceed plasma binding affinity and therefore drug will be stripped from its plasma binding sites during its passage through the liver. For drugs with a high extraction ratio, plasma protein binding, by maintaining high total drug levels within the bloodstream, will make more drug available for biotransformation by diminishing its diffusion to more distant tissues. It acts as a transport mechanism carrying drug to its site of destruction. Metabolism of highly extracted drugs, for example propranolol, is therefore blood flow-dependent 15

16. For drugs with a low extraction ratio, only free drug will be available for metabolism and hence plasma protein binding may afford a protective role upon the intact drug. Metabolic clearance will be directly proportional to the free fraction of drug in the plasma Renal Elimination : Only unbound drug is free for filtration in the glomerulus and therefore, high plasma protein binding will help retain a drug in the body. Plasma protein binding can further decrease the rate of elimination of a drug that is lipid soluble at the pH of tubular fluid by maintaining a high concentration gradient for back diffusion of drug from the glomerular filtrate into the bloodstream. Like the active component of metabolism, renal tubular secretion generally is not limited by plasma protein binding. This means that for drugs which are highly cleared by the kidney due to tubular secretion (e.g. penicillins ), plasma protein binding may act as a transport mechanism and thus aid drug elimination Biliary Excretion : A high affinity for albumin binding predisposes a drug towards biliary excretion. Highly bound drugs can undergo rapid biliary excretion 16

17. Competition Between Drugs for Binding Sites The addition of another drug to a primary drug regimen can result in drug displacement either at plasma binding sites, tissue binding sites, or in both areas. This will give rise to changed kinetics of both drugs and, in certain instances, changed drug effects in the patient Displacement from albumin binding sites will depend on the affinity of the interacting drugs for binding sites and on the position of the binding sites on the albumin molecule. If two drugs are bound at the same sites on the albumin molecule there will be a mutual competition between the drugs for these binding sites. The drug with the larger association constant will displace the drug with the lower association constant for the same binding sites, e.g. phenylbutazone competitively displaces warfarin from its albumin binding. 17 PLASMA BINDING DISPLACEMENT

18. In this type of interaction, phenylbutazone is termed the displacing agent while warfarin is termed the displaced drug. However, the binding of both drugs involved in a competitive type interaction will be decreased. Parent drugs may themselves not take part in the competitive displacement but rather their metabolites may be involved. this was clearly demonstrated in the interaction between chloral hydrate and warfarin. Original data suggested that increased anticoagulation was due to displacement of warfarin from its albumin binding by chloral hydrate. It was subsequently discovered, however, that it was not the parent drug, but its metabolite trichloroacetic acid which gave rise to warfarin displacement Non-competitive binding inhibition can also take place at plasma binding sites, A drug by its binding to, for example, albumin may change the physical chemistry of the macromolecule giving rise to tertiary conformational changes of the albumin which may change the shape of specific binding sites of other drugs. Aspirin influences the binding of certain drugs, e.g. flufenamic acid and phenylbutazone , by a noncompetitive mechanism; it permanently acetylates the lysine residues of albumin 18

19. Tissue binding interaction A drug can bind to one or more of the several tissue components. Tissue – drug binding is important in distribution from two viewpoints: It increases the apparent volume of distribution of drugs in contrast to plasma protein binding which decreases it. This is because the parameter is related to the ratio of amount of drug in the body to the plasma concentration of free drug and the latter is decreased under conditions of extensive tissue binding of drugs. Tissue – drug binding results in localization of a drug at a specific site in the body (with a subsequent increase in biological half life). This is more so because a number of drugs bind irreversibly with the tissues ( contrast to plasma protein – drug binding); for example, oxidation products of paracetamol , phenacetin , chloroform, carbon tetrachloride and bromobenzene bind covalently to hepatic tissues. 19

20. Factors affecting Drug Distribution among various Tissues Tissue Permeability of the Drug a.) Physiochemical Properties of the Drug like Molecular size, pKa and o/w Partition Coefficient. b.) Physiological Barriers to Diffusion Of Drugs. Organ/Tissue Size and Perfusion Rate Miscellaneous Factors 20

21. Tissue Permeability of the Drugs depend upon : Rate of Tissue Permeability Rate of Blood Perfusion The Rate of Tissue Permeability depends upon Physiochemical properties of the drug as well as Physiological Barriers that restrict the diffusion of drug into tissues Physiochemical properties that influence drug distribution are: i .) Molecular Size ii.) pKa iii.) o/w partition coefficient Drugs having molecular weight less than 400 Daltons easily cross the capillary membrane to diffuse into the extracellular interstitial Fluids. The penetration of Drug from the Extracellular fluid (ECF) is a function of : Molecular Size Ionisation 21

22. Lipophilicity Organ/Tissue Size and Perfusion Rate Miscellaneous Factors AGE Pregnancy Obesity DISEASE STATE: Alteration or reduced perfusion to organ or tissue Altered tissue pH Altered albumin & other drug binding protein concentration Alteration of permeability of physiological barrier (BBB). 22

23. Pharmacokinetic Consequences of Tissue binding Tissue binding is a major determinant of drug distribution in terms of both volume of distribution and site-specific localization. If only free drug is available for excretion, metabolism, receptor interaction, or other cellular processes, then the transport processes are called restrictive . This is the case when free drug is transported across a permeability barrier together with its osmotic share of plasma water, so that the remaining free concentration is unchanged. A non-restrictive transport is characterised by the free drug being transported selectively through a membrane i . e. , out of the plasma water rather than with it . Non-restrictive transports occur wherever binding or disappearance of the drug creates a concentration gradient or a so-called “sink effect”. 23

24. In such a case, the free concentration before the permeability barrier decreases and the disturbed binding equilibrium will be restored by dissociation of drug-protein complex. Thus, in this type of transport process, total drug concentration (free and bound) becomes available — i.e . , the availability is not restricted to free drug. If displacement of tissue -bound drug were to occur, then this would result in a decrease of the apparent volume of distribution . This contrasts with displacement of plasma-bound drug which results in increased volumes of distribution. The simplest expression which relates volume of distribution to tissue binding is given by: V D(tot) = V pl + V tiss . f f ( pl ) f f ( tiss ) where, V pl = Plasma volume V tiss = volume of the other body tissue water f f = free fractions in plasma and tissue respectively The volume of distribution increases with increasing tissue binding. 24

25. In contrast to distribution, clearance as irreversible removal of drug is not influenced by tissue binding. On the other hand, elimination half-life is a function of both clearance and volume of distribution and hence can be influenced by tissue binding. Nonlinear or concentration-dependent tissue binding is likely to occur at high drug concentrations and high volumes of distribution . 25

26. Binding Competition Drugs that bind to both tissue and plasma components result in competition between drug binding sites. Overall distribution (volume of distribution VD) results from a binding competition between tissue and plasma. Increasing the plasma-bound fraction of a drug from 0 to 1 in the absence of tissue binding would lead to a decrease of VD from total body water volume to plasma volume. In contrast, increasing the tissue -bound fraction from 0 to 0. 99 would lead to a dramatic increase of apparent VD. Binding competition can be simulated and studied by a simple in vitro technique named distribution dialysis When equilibrium dialysis is used for the purpose of binding studies, then a drug or other ligand is dialyzed against plasma, an individual protein, or other binders . Once diffusion equilibrium is reached, the free and bound drug concentrations can be determined. By contrast, in the distribution dialysis technique, both dialysis chambers contain a binder, and a drug is allowed to distribute between the two different binding systems . Distribution is then expressed as drug concentration ratio of the two chambers e . g. , concentration ratio intracellular / extracelIular preparation if a tissue preparation and plasma are used 26

27. Adipose Tissue Storage of Drugs Extensive tissue – drug binding suggests that a tissue can act as the storage site for drugs. Accumulation of drugs in tissues or body compartments can prolong drug action because the tissues release the accumulated drug as plasma drug concentration decreases. For example, thiopental is highly lipid soluble, rapidly enters the brain after a single IV injection, & has a marked & rapid anesthetic effect. The effect ends within a few minutes as the drug is redistributed to more slowly perfused fatty tissues. Thiopental is then slowly released from fat storage, maintaining subanesthetic plasma levels . These levels may become significant if doses of thiopental are repeated, causing large amounts to be stored in fat . Thus, storage in fat initially shortens the drug’s effect but then prolongs it. 27

28. For majority of drugs that bind to extravascular tissues the order of binding is: Liver > Kidney > Lung > Muscles Examples of Extravascular tissue – drug binding are 28

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31. SIGNIFICANCE OF PROTEIN/TISSUE BINDING OF DRUGS Absorption Systemic solubility of drugs Distribution Tissue binding, apparent volume of distribution and drug storage Elimination Displacement interaction and toxicity Diagnosis Therapy and drug targeting 31

32. Cytochrome p450 based drug intreaction Cytochromes P450 (CYPs) are a  superfamily of enzymes  containing  heme  as a cofactor that function as  monooxygenases . The enzymes are heme -containing membrane proteins, which are located in the smooth endoplasmic reticulum of several tissues. Although a majority of the isozymes are located in the liver, extrahepatic metabolism also occurs in the kidneys, skin, gastrointestinal tract, and lungs . Officially abbreviated as CYP Is a large and diverse group of enzymes that catalyse the oxidation of organic substances They absorb light at a wavelength of 450 nm 32

33. What they do? Cytochrome P450 (CYP450) enzymes are essential for the production of cholesterol, steroids , prostacyclin , and thromboxane A 2 . They also are necessary for the detoxification of foreign chemicals. There are more than 50 CYP450 enzymes, but the major 6 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 metabolize 90% of drugs. These enzymes are predominantly found in the liver , but they also present in the small intestine, lungs, placenta, and kidneys. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in drug-drug interactions that can cause adverse reactions or therapeutic failures . Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the cytochrome P450 enzymes. 33

34. Drug Interactions based on CYP Case 1 - The non-sedating antihistamines terfenadine and astemizole and the gastrointestinal motility agent cisapride were all withdrawn from the U.S. market because metabolic inhibition by other drugs led to life-threatening arrhythmias . Case 2 - The Mibefradil (CCB) was withdrawn from the U.S. market in 1998 because it was a potent enzyme inhibitor that resulted in toxic levels of other cardiovascular drugs . Case 3 - CYP450 inhibitor is combined with a prodrug (e.g. Losartan) , or a person is a poor metabolizer of a prodrug , therapeutic failure is likely to result because of little or no production of the active drug. 34

35. Drugs interact with the CYP450 system in several ways. Drugs may be metabolized by only one CYP450 enzyme (e.g., Metoprolol by CYP2D6) or by multiple enzymes ( e.g., warfarin by CYP1A2, CYP2D6, and CYP3A4). Drugs that cause CYP450 metabolic drug interactions are referred to as either inhibitors or inducers. CYP Inhibitors: Drugs which decreases the metabolism of other drugs by Inhibiting CYP enzymes. (These will slow down substrate drug metabolism and increase drug effect) Inhibitory effects usually occur immediately. CYP Inducers: Drugs which increases the metabolism of other drug in the body. (These will speed up substrate drug metabolism and decrease drug effect) Inducing effect usually occur delayed . Substrate : The substance on which an enzyme acts (Drugs behave as   substrates). 35

36. CYP Inhibitors Inhibitors block the metabolic activity of one or more CYP450 enzymes. The extent to which an inhibitor affects the metabolism of a drug depends upon factors such as the dose and the ability of the inhibitor to bind to the enzyme. sertraline (Zoloft) is considered a mild inhibitor of CYP2D6 at a dose of 50 mg, but if the dose is increased to 200 mg, it becomes a potent inhibitor. Inhibitory effects usually occur immediately. A Drug can: Be a substrate & Inhibitor of the same enzyme (e.g. Erythromycin ) Be metabolized by one enzyme and inhibit another enzyme (e.g., Terbinafine ). Be intentionally combined to take advantage of CYP450 inhibition. (e.g. Ritonavir added to lopinavir to decrease the degradation by CTP3A4 to improve therapeutic activity in patients with HIV. 36

37. CYP Inducers Inducers increase CYP450 enzyme activity by increasing enzyme synthesis. Usually effect is delayed. e.g Decreased substrate concentration within 24 hours ( Rifampin - short half life inducer) Or upto 1 week (Phenobarbital- Long half life inducer) A Drug can: Be a substrate & inducer at the same time (e.g. Carbamazepine ) ( Carbamazepine- A potent enzyme inducer, must be initiated at a low dose and then increased at weekly intervals as its half-life gradually decreases over time) Induce other enzymes 37

38. Cytochrome P450 Enzymes and Their Inhibitors, Inducers, and Substrates 38

39. Common Drug-Drug Interactions Involving the Cytochrome P450 Enzyme System 39

40. Transporters-drug intreaction Drug transporters are expressed in various tissues and play a significant role in transporting drugs into and out of cells. Therefore, competition for the same transport pathways among coadministered drugs can cause a significant change in drug absorption, tissue distribution, metabolism and excretion profiles. Consequently , the resulting pharmacokinetics of drug interactions alter drug levels (decreases or increases in blood and tissue concentrations of drugs) and change the safety and efficacy profiles of a drug. The clinical concern in this case becomes the loss of effectiveness of drugs or an increase in undesired adverse drug reactions, particularly for drugs having a narrow therapeutic index 40

41. Membrane transporter Transporters are the specialised membrane spanning proteins that assist in the movement ions ,peptides ,small molecules, lipids, and macromolecules across biological membrane. Functionally they can be classify into transporters mediating uptake of drugs into cells and the transporters that mediating the export of the drugs or drug metabolites out of cell. 1) uptake transporters 2) efflux transporters 41

42. 1) Uptake transporters Members of the solute carrier (SLC) family. Mediating the transport of substances from outside into cells. Members are 1. OAT : organic anion transporter 2. OCT : organic cationic transporter It transport variety of amphipathic substances metabolites like bile acids ,thyroid hormones ,antibiotics 42 2) EFFLUX TRANSPORTERS Members of the ATP binding cassette transports family. Export proteins transporting substance out of cells. Members : 1. MDR : multi drug resistance protein 2. MRP2 PROTIEN 3. P-GP 4. MATE

43. Drug Interaction linked to Transporters Aliskiren is substrate of p- gp . When it administered with itraconazole its plasma concentration is increase because the itraconazole is inhibitor of p- gp . When aliskiren is administered with the rifampicin it cause reduction in concentration of aliskiren because rifampicine is inducer of p- gp protein which is efflux protein Rifampicine when administered with the oral digoxin it reduce the bioavailability of the digoxin because it cause induction of pgp protein which cause efflux of the oral digoxin. Because of this reason it cause reduction in bioavailability of the digoxin. The fibrate gemfibrozil and its metabolite are the inducers of OATP1B1 , OATP1B3. when they use with a pravastatin it cause the increase in AUC of pravastatin. 43

44. Concomitant administration of quinidine or verapamil reduce the biliary digoxin clearance in human by approximately 45%. Quinidine and verapamil are the potent inhibitors of p- gp mediated digoxin transport.so the biliary excretion of digoxin was significantly decreased. MATE is efflux transporter it cause efflux of drug like metformin but when they give combine with pyrimethamine it cause inhibition of MATE and efflux of metformin decrease which cause increase the concentration of the drug Uricosuric drug probenecid is inhibitor of the organic anion transporters OAT1 and OAT3. Benzylpeniciline is substrate for OAT3. When they coadministred probenecid enhance or prolong half life of antibiotic Benzylpeniciline . Itraconazole and cyclosporine also inhibitor of pgp so when it given with digoxin it enhance the concentration of digoxin due to inhibition of efflux transporter pgp . The major route of the elimination of benzylpenicillin , renal tubular secretion, is efficiently inhibited by probenecid 44

45. Benzylpenicillin is a substrate of OAT3 [138], and probenecid was identified as being a clinically relevant inhibitor of OAT1 and OAT3. For the inhibition of OAT1- and OAT3-mediated cellular uptake by probenecid and it cause prolong half life of Benzylpeniciline . probenecid decreased the renal clearance of methotrexate and furosemide A beneficial interaction that reduces the risk of adverse drug reactions has been described for the combination of probenecid and cidofovir . The use of the antiviral drug cidofovir is limited owing to its pronounced renal toxicity , cidofovir is transported by OAT1. addition of probenecid inhibits cidofovir uptake and cytotoxicity because probenecid is inhibitor of the organic anion transporters OAT1 and OAT3 45

46. Thank you 46