Pharmacokinetics: An overiew

Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement of drug into, through, and out of the body—the time course of its absorption, bioavailability, distribution, metabolism, and excretion.

1. Pharmacokinetics Prof. Amol B Deore MVP’s Institute of Pharmaceutical Sciences, Nashik (INDIA)

2. In order to get its effect, a drug must be administered in a suitable dosage form at appropriate site. It must be absorbed effectively from the site of administration, and distributed in the body to reach its site of action. After its action, for the termination of its effect, the drug must be metabolized , and its metabolites excreted from the body.

3. Pharmacokinetics Pharmacokinetics is study of the movement of drug molecules in body. It includes absorption, distribution, metabolism and excretion of drug (ADME). In short, pharmacokinetics means what body does to the drug.

4. Drug absorption Absorption is movement of the drug from its site of administration into the circulation. Simply speaking, absorption is the entry of drug molecules into blood via mucous membrane of digestive organs, or respiratory tract or from site of injection. When a drug is administered orally, it passes through the mucus membrane of G.I.T. organs and blood capillary membrane to enter in to the blood circulation. When drug is given intravenously, it enters directly in to blood.

5. Process of drug absorption on oral administration Oral preparation Disintegration Granules Deaggregation Fine particles dissolution Solution Absorption

6. Cell membrane Biological cell membrane is a lipoprotein membrane. The lipid portion of membrane is bilayer (double layer) and made up of phospholipid and cholesterol molecules. The proteins are located across the lipid bilayer. The membrane contains many aqueous pores (channels) though which filtration of small drug molecules occur.

7. structure of cell membrane

8. Drugs may cross body membranes by following mechanisms Passive diffusion Filtration Active transport Facilitated diffusion Endocytosis

9. Passive diffusion The lipid soluble drug can cross the cell membrane easily by diffusion. e.g. diazepam, propranolol etc. the drug molecules cross the cell membrane by dissolving in lipid bilayer of membrane. The rate of drug transfer is directly proportional to lipid/water coefficient. Greater the coefficient of drug, faster the diffusion of the drug through the membrane.

10. Filtration Filtration is passage of drugs through aqueous pores in the membrane or through paracellular spaces. This can be accelerated if hydrodynamic flow of the solvent is occurring under hydrostatic or osmotic pressure gradient, e.g. across most capillaries including glomeruli. Lipid-insoluble drugs cross biological membranes by filtration if their molecular size is smaller than the diameter of the pores.

11. Active transport It means the passage of drug across the biological membrane against their concentration gradient with the help of carriers by the use of energy (ATP). e.g. methyl dopa , levodopa, 5-fluoro-uracil. It involves movement of drug molecules from lower to higher concentration. It is carrier mediated i.e. carries by a specific transport protein.

12. Facilitated diffusion It means the passage of drug across the biological membrane along the concentration gradient by the protein carrier mediated system also called as carrier mediated diffusion. It depends on number of carrier e.g. absorption of glucose, iron and amino acids from intestine.

13. Endocytosis It is the process by which the large molecules are engulfed by the cell membrane and releases them intracellularly e.g. protein, toxins

14. Factors affecting drug absorption

15. Local PH of GIT organs Most of the drugs are weak acids or bases and at the physiological pH of body fluids (7.4), drug molecules exist as mixture of ionized (charged) and unionized (free) molecular form. It is observed that, drugs which are more lipid soluble exist as unionized form; whereas water soluble drugs are exist in ionized form. The principle is that: “Cell membranes are more permeable to unionized form of a drug than to an ionized form .”

16. For examples: Acidic drugs like phenobarbitone and aspirin would be in unionized form at low pH of stomach. Hence these drugs are significantly absorbed from stomach. Basic drugs like amphetamine and morphine would be in ionized form at the low pH of stomach and not well absorbed. As these drugs move down in the intestine, the pH increases and acidic drug become more ionized, whereas basic drugs are less ionized. Therefore absorption of basic drugs increases as the molecules move through the intestine.

17. Presence of food and other drug in GIT Most drugs are better absorbed in empty stomach but they may cause gastric irritation, nausea, vomiting, gastric bleeding and ulcer. Presence of food in the stomach dilutes the drug and retards absorption of drug. e.g. ampicillin, aspirin. The presence of other drugs in GIT may increase or decrease the absorption of drug due to drug-drug interaction. e.g. Vitamin C enhances the absorption of iron from the G.I.T. Calcium present in milk and in antacids forms insoluble complexes with the tetracycline antibiotics and reduces their absorption.

18. Surface area of GIT organs The greater the surface area of the absorbing surface, the faster is the rate of absorption. Drugs are better absorbed from the small intestine than the stomach due to greater surface area.

19. Disease states of GIT organs Absorption and first pass metabolism may be affected in conditions like malabsorption , thyrotoxicosis, achlorhydria and liver cirrhosis.

20. GIT motility Increase in G.I.T. motility as in diarrhoea, decreases absorption of drugs due to rapid elimination in faeces. Vomiting also decreases absorption of drugs.

21. First pass metabolism Some drugs e.g. nitroglycerin , isoprenaline , propranolol, chlorpromazine etc. undergo first pass metabolism in G.I.T. and liver during hepatic portal circulation. It decreases their therapeutic effect. These drugs are better administered sublingually to reach the systemic circulation.

22. Physical state of drug Drugs given in liquid dosage form are better and rapidly absorbed from G.I.T. than when given in solid dosage forms.

23. Water or lipid solubility of drug The biological cell membrane, mucous membrane and blood capillary membrane are made up of lipid bilayer. The principle is that: “Cell membranes are more permeable to unionized form of a drug than to an ionized form.” If the drug is lipid soluble then its greater fraction exists in unionized form. Therefore lipid soluble drugs are absorbed better and greater extent because cell membranes are more permeable to unionized form of a drug. If the drug is water soluble then its greater fraction exists in ionized form. Hence because of ionization water soluble drugs poorly absorbed.

24. Chemical stability Chemically unstable drugs are inactivated in gastrointestinal tract. Penicillin-G is unstable in acid medium (acid labile) of stomach and cannot produce satisfactory results on oral administration. But penicillin-V is more stable in acid medium of stomach (acid resistant) than penicillin-G and therapeutically effective.

25. Molecular weight Drugs with high molecular weight are not usually absorbed from gastrointestinal tract on oral administration. Such drugs may be inactivated by enzymatic degradation. e.g. insulin undergoes enzymatic degradation in G.I.T. and not effectively absorbed. Hence insulin is given subcutaneously.

26. Particle size of drug Solid dosage form of drugs that contain smaller particles are better absorbed from G.I.T. e.g. aspirin, tolbutamide , griseofulvin . Smaller the particle size of drug better will be the drug absorption. Solid dosage form of drugs that contain larger particles e.g. streptomycin, neomycin are very little absorbed from G.I.T.

27. Bioavailability Bioavailability refers to the rate and extent of absorption of a drug from a dosage form. It is a measure of the fraction (F ) of administered dose of a drug that reaches the systemic circulation. Bioavailability of drug injected i.v. is 100%, but is frequently lower after oral ingestion because- 1) the drug may be incompletely absorbed. 2) the absorbed drug may undergo first pass metabolism .

28. Single dose bioavailability test involves an analysis of plasma or serum concentration of the drug at various time intervals after its oral administration and plotting a serum concentration time curve. AUC after oral dose AUC after I.V. dose X 100 Bioavailability =

29. DRUG DISTRIBUTION Drug distribution is the process which transports a drug to its site of action, to other storage sites in the body, and to the organs of metabolism and excretion.

30. The main factors which affect drug distribution are physiochemical characteristics of the drug route of drug administration plasma proteins binding of drug regional blood flow  

31. Plasma proteins binding of drug After drug get absorbed or injected into systemic blood circulation, It is distributed in various body fluid compartments such as interstitial fluid, intracellular fluid, cerebrospinal fluid, lymph, endolymph , GIT fluid, aqueous humour, and plasma. The plasma and these body fluids contain plasma proteins albumin , globulin and glycoprotein . The drug molecules bound to plasma proteins until the equilibrium is formed with unbound drug (free form) in plasma. But the only free drug exerts a pharmacological action.

32. Drug bound to proteins forms drug: plasma protein complex. This complex does not show pharmacological action, because it cannot cross cellular membrane to interact with its site of action. Hence Drug: plasma protein complex acts as drug reservoir . Protein binding slows down (delay) the drug excretion. Only free drug capable of crossing cell membrane can show their pharmacological action.

33. As free drug molecules undergo metabolism and excretion, drug: plasma protein complex dissociates to supply more free drug molecules. There are a large number of drugs which are more than 90% bound to plasma albumin, e.g . doxycycline, warfarin, indomethacin, propranolol, chlorpropamide , imipramine and phenytoin.

34. METABOLISM OF DRUGS The process of alteration in chemical structure of drug molecule is referred as drug metabolism or biotransformation. Drugs treated by the body as foreign substances, which body tries to remove from the body by metabolism and excretion.

35. The sites for drug metabolism are liver, kidney, gastrointestinal tract, lungs and plasma. The metabolism generally results in the conversion of a drug to a metabolite that is less active, less lipid soluble, less toxic and hence easily excreted.

36. Enzymes responsible for metabolism of drugs: a) Microsomal enzymes: Present in the smooth endoplasmic reticulum of the liver, kidney and GIT e.g. glucuronyl transferase , dehydrogenase , hydroxylase and cytochrome P450. b) Non-microsomal enzymes: Present in the cytoplasm, mitochondria of different organs. e.g. esterases , amidase , hydrolase.

37. Types of biotransformation The chemical reactions involved in biotransformation are classified as phase-I and phase-II (conjugation) reactions. In phase-I reaction the drug is converted to more polar metabolite.

38. If this metabolite is sufficiently water soluble, then it will be excreted in urine. Some metabolites may not be excreted and further metabolised by phase –II reactions. Phase-I : Oxidation (hydroxylation, dealkylation , deamination, dehalogenation , sulfoxide formation), reduction and hydrolysis. Phase-II: Glucuronidation , sulfate conjugation, acetylation, glycine conjugation and methylation reactions.

39. First pass metabolism First pass metabolism is a process in which a drug administered by mouth is absorbed from the gastrointestinal tract and transported via portal vein to liver, where it is metabolized. As a result only a small fraction of the active drug enters into systemic circulation and available at its site of action. First pass metabolism reduces bioavailability of drug. First pass metabolism can be bypassed by giving the drug via sublingual or other route. E.g. metoprolol , imipramine, cimetidine, diazepam, nitroglycerin etc.

40. DRUG EXCRETION Excretion of drugs means the transportation of drug metabolite out of the body. The major processes of excretion include renal excretion, biliary excretion and pulmonary excretion. The minor routes of excretion are saliva, sweat, tears, breast milk, vaginal fluid, and hair.

41. 1) Renal excretion: The excretion of drug by the kidney involves three stages- Glomerular filtration: some drugs and drug metabolites undergo ultrafiltration in glomerulus and enter into glomerular filtrate. All the drugs which have low molecular weight (5000-69000) can filter through glomerulus. Only the free form of drug (which is not bound with the plasma proteins) can pass through glomerulus . e.g. phenobarbitone , digoxin, ethambutol etc.

42. Tubular reabsorption: The reabsorption of drug takes place from the distal convoluted tubules into plasma. The unionized and lipid soluble drugs in the glomerular filtrate rapidly and completely reabsorbed into blood. Tubular secretion: The cells of the proximal convoluted tubule transport drugs from the plasma into the tubule e.g. sulpha drugs, cephalosporin, acetazolamide, penicillin-G, dopamine, pethidine , thiazides etc.

43. Biliary excretion: Molecular weight more than 300 daltons and polar drugs are excreted in the bile. After excretion of drug through bile into intestine, and then excreted in the faeces. e.g. chloramphenicol

44. Gastrointestinal excretion: When a drug is administered orally, a part of the drug is not absorbed and excreted in the faeces. e.g. aluminium hydroxide, ferrous sulphate.

45. Pulmonary excretion: Drugs that are readily vaporized, such as many inhalation anaesthetics and alcohols are excreted through lungs. E.g. general anaesthetics, alcohol

46. Sweat A number of drugs are excreted into the sweat e.g. rifampicin, metalloids like arsenic and other heavy metals.

47. Mammary excretion: Many drugs mostly weak basic drugs are accumulated into the milk. They may enter into baby through breast milk and produce harmful effects in the baby e.g. ampicillin, aspirin, chlordiazepoxide , tetracycline, diazepam, furosemide, morphine, streptomycin etc.

48. The End