General Pharmacology- Pharmacokinetics.pptx

P'cology

1. General Pharmacology: Part 1 Pharmacokinetics

2. Pharmacokinetics Quantitative study of drug movement in, through and out of the body Intensity of response depends on drug conc. at site of action Which depends on its pharmacokinetic properties P’kinetic considerations determine: Route(s) of administration Dose Latency of onset Time of peak action Duration of action Frequency of administration

3. Transport Across Biological Membrane Biological membrane: Bilayer of phospholipid and cholesterol molecules About 100 angstrom thick Polar groups oriented at the two surfaces Non-polar hydrocarbon chains embedded in the matrix Form continuous sheets High electrical resistance and relative impermeability Extrinsic and intrinsic protein molecules absorbed in bilayer Drugs transported by Passive diffusion & filtration Specialized transport

4. Transport Across Biological Membrane

5. Passive Diffusion Drug diffuses across the membrane In the direction of concentration gradient Membranes play no active role Most important mechanism for majority of drugs Lipid-soluble drugs diffuse by dissolving in lipoidal matrix of membrane More lipid-soluble: Higher conc. in membrane, quick diffusion Greater the concentration gradient, faster is the diffusion

6. Passive Diffusion Most drugs are weak electrolytes Ionization is pH-dependent Weakly acidic drugs ionize more at alkaline pH 1 scale change in pH: 10-fold change in ionization Weakly basic drugs ionize more at acidic pH Ions are lipid-insoluble: Don’t diffuse pH difference across a membrane can cause differential distribution

7. Passive Diffusion Acidic drugs (e.g. Aspirin): Largely unionized at gastric pH Absorbed from stomach Basic drugs (e.g. Atropine): Absorbed only when they reach intestine Unionized form of acidic drugs crosses gastric mucosal cell membrane Reverts to ionized form within the cell Slowly passes to extracellular fluid “Ion trapping ” May contribute to Aspirin-induced gastric mucosal damage

8. Passive Diffusion Basic drugs attain higher concentration intracellularly pH 7.0 vs. 7.4 of plasma Acidic drugs are ionized more in alkaline urine Don’t back-diffuse in kidney Excreted faster Basic drugs excreted faster through acidified urine Lipid-soluble non-electrolytes (e.g. Ethanol) readily cross membranes pH-independent transport

9. Filtration Passage of drugs through aqueous pores in membrane Or through paracellular spaces Lipid-insoluble drugs cross if molecular size is smaller than pore Most cells have very small pores (4 angstrom) Drugs with MW >100 or 200 cannot penetrate Capillaries (except those of brain) have large paracellular spaces (40 Å) Most molecules (including albumin) can penetrate This depends on rate of blood flow through capillaries

10. Passive Diffusion and Filtration

11. Specialized Transport: Carrier Transport All cell membranes express a host of trans-membrane proteins Serve as carriers or transporters for important ions, nutrients etc Certain transporters also translocate xenobiotics Including drugs and their metabolites Combine transiently with substrate Undergo conformational change Carry the substrate to the other side; substrate dissociates Transporter returns to its original state

12. Specialized Transport: Carrier Transport Carrier transport characteristics Specific for a substrate (or type of substrate, e.g. organic anion) Saturable Competitively inhibited by analogues using same transporter Much slower than flux through channels Two types Facilitated diffusion Active transport

13. Facilitated Diffusion Transporter belongs to the super-family of SLC transporters Operates passively without needing energy Translocates substrate in the direction of concentration gradient Facilitates permeation of a poorly soluble substrate Entry of glucose into muscles and fat cells by GLUT-4

14. Active Transport Transport the solute against concentration gradient Selective accumulation of substance on one side of the membrane Requires energy Inhibited by metabolic poisons Drugs related to normal metabolites can use transport meant for these Levodopa is absorbed from gut by aromatic amino acid transporter Some relatively non-selective receptors like P-glycoprotein Active transport can be primary or secondary Depending on the source of driving force

15. Primary Active Transport Energy is obtained directly by ATP hydrolysis Transporters belong to super-family of ABC transporters Intracellular loops have ATPase activity Mediate only efflux from cytoplasm To extracellular fluid To an intracellular organelle (endoplasmic reticulum, mitochondria) P-gp is most well-known Pumps out many drugs/metabolites Limits absorption from intestine; penetration to brain, testes Promotes biliary and renal elimination

16. Secondary Active Transport Effected by another set of SLC transporters Energy is derived from downhill movement of another solute Mostly Na + Symport (co-transport): Both solutes move in same direction Antiport (exchange transport): Both move in opposite directions Energy obtained from ATP hydrolysis Spent in maintaining high electrochemical gradient of second solute Transporters mediate uptake and efflux of drugs/metabolites

17. Secondary Active Transport Secondary active transporters important for metabolism and excretion Organic anion transporting polypeptide (OATP) Organic cation transporter (OCT) Vesicular monoamine transporter (VMAT-2) On adrenergic and serotonergic vesicles Transports catecholamines and 5-HT into vesicles By exchange with H + ions Inhibited by Reserpine Absorption of glucose in intestine and renal tubules: SGLT1 & SGLT2

18. Secondary Transport: All Types of Carrier Transport Facilitated diffusion Primary active transport Symport Antiport

19. Specialized Transport: Vesicular Transport Exocytosis and Endocytosis Substances with very large/impermeable molecules transported this way Enclosing their particles into tiny vesicles Binding protein located on membrane complexes with the substance Initiates vesicle formation Vesicle detaches from the membrane May remain stored within the cell May release the substance into cytoplasm May move to opposite membrane, fuse with it Release the substance across the cell

20. Specialized Transport: Vesicular Transport Exocytosis and Endocytosis Applicable to proteins and other large molecules Contributes little to transport of most drugs Except a few like vitamin B 12 Absorbed from gut after binding to “intrinsic factor” (a protein) Most hormones and neurotransmitters secreted/released by exocytosis Activation of secretory cell/nerve ending prompts vesicle fusion to surface Followed by extrusion of contents into extracellular space

21. Specialized Transport: Vesicular Transport Exocytosis and Endocytosis

22. Absorption

23. Absorption Movement of drug Site of administration to circulation Fraction absorbed as well as rate of absorption Drug has to cross biological membrane Unless given IV

24. Factors Governing Absorption Aqueous solubility Solid: Must dissolve in aqueous biophase Poorly soluble drugs: Rate of dissolution governs rate of absorption Drug given as watery solution absorbs faster Concentration Passive diffusion depends on concentration gradient Area of absorbing surface Larger the surface area, faster the absorption

25. Factors Governing Absorption Vascularity of absorbing surface Blood circulation removes the drug from site of administration Maintains the concentration gradient Increased blood flow hastens the absorption Route of administration Each route has its own peculiarities

26. Absorption Following Oral Administration Epithelium of GI tract (lipoidal): effective barrier Non-ionized lipophilic drugs readily absorbed From stomach as well as intestine Rate proportional to lipid-water partition coefficient Acidic drugs absorbed from stomach Still slow: mucosa is thick, covered in mucus, less surface area Alkaline drugs absorbed from intestine Faster gastric emptying accelerates the absorption in general

27. Absorption Following Oral Administration Dissolution is a surface phenomenon Particle size governs rate of dissolution and absorption Presence of food dilutes the drug: retards absorption Some drugs form poorly absorbed complexes with food constituents Tetracycline with calcium in milk Most drugs absorbed better with empty stomach Some exceptions: Fatty food enhances Lumefantrine absorption Highly ionized drug absorbed poorly

28. Absorption Following Oral Administration Some drugs are degraded in GI tract: ineffective orally Penicillin G degraded by acid Insulin degraded by peptidases Enteric coated tablets and sustained release formulations to combat this Some drugs are extruded back into lumen by P-gp Partly responsible for low oral bioavailability of Digoxin P-gp inhibitors enhance their absorption P-gp inducers decrease absorption Effect on gut wall can also alter absorption Altering motility or causing mucosal damage

29. Absorption Following SC and IM Administration Drug deposited directly in the vicinity of capillaries Lipophilic drugs pass readily across the endothelium Large paracellular spaces: No obstruction to large lipid-insoluble molecules Very large molecules absorbed through lymphatics Many drugs not absorbed orally are absorbed this way Absorption from SC generally slower than IM Both faster and more consistent/predictable than oral

30. Absorption Following SC and IM Administration Heat and muscular exercise accelerate absorption Increase blood flow Vasoconstrictors retard absorption Hyaluronidase incorporation facilitates absorption from SC site Promoting spread Many depot preparations can be given this way Benzathine penicillin, depot progestins

31. Absorption from Topical Sites Depends primarily on lipophilicity Very few drugs significantly penetrate the skin Hyoscine, Fentanyl, GTN, Nicotine, Testosterone, and Estradiol used Corticosteroids applied over extensive areas Systemic effects Pituitary-adrenal suppression Absorption can be promoted by rubbing the drug having olegenous base Also by occlusive dressing: Increases skin hydration

32. Absorption from Topical Sites Organophosphate insecticides on skin can produce systemic toxicity Abraded surfaces readily absorb drug Tannic acid over burnt skin: hepatic necrosis Cornea is permeable to lipophilic unionized Physostigmine Not to highly ionized neostigmine Drugs in eye drops may get absorbed through nasolacremal duct Timolol eye drops may produce bradycardia and precipitate asthma Mucous membranes of mouth, rectum, vagina absorb lipophilic drugs Vaginal estrogen has produced gynaecomastia in male partner

33. Bioavailability Rate and extent of absorption of drug from a dosage form Administered by any route Determined by its concentration-time curve in blood Or by excretion in urine Measure of fraction (F) of administered dose reaching circulation In unchanged form Bioavailability after IV administration is 100% Frequently lower after oral administration Incomplete bioavailability after SC/IM injection is less common May occur due to local binding of drug

34. Bioavailability

35. Bioequivalence Bioequivalent preparations: Rate and extent of bioavailability isn’t significantly different Differences mostly seen with poorly soluble and slowly absorbed drugs May arise due to different disintegration and dissolution rates Microfine tablets of Aspirin: increased rate of absorption Amount of Griseofulvin can be reduced to ½ if microfined No need to reduce the particle size of freely water-soluble drugs

36. Bioequivalence Bioavailability variations significant for drugs with low safety margine E.g. Digoxin Also where dosage needs precise control E.g. Oral hypoglycaemics, oral anticoagulants May also be responsible for success/failure of antimicrobial For many drugs, bioavailability differences are negligible Risk of changing from a brand to another brand/generic often exaggerated

37. Distribution

38. Distribution Once in the blood stream, drug gets distributed to other tissues Concentration gradient in the direction of plasma to tissues Extent and pattern of distribution depends on Lipophilicity Ionization at physiological pH Extent of plasma & tissue protein binding Presence of tissue-specific transporters Differences in regional blood flow

39. Distribution Drug movement persists until equilibrium is established Between unbound drug in plasma and tissue fluids Subsequently, parallel decline in both due to elimination Apparent volume of distribution (V) Presume that body behaves as a single homogeneous compartment Drug distributed into volume V immediately and uniformly

40. Distribution For example, 1000 mg of drug given IV attains 50 mg/L conc. V = 1000/50 = 20 L The drug doesn’t actually distribute into 20 L of body water So, this is only apparent volume of distribution “The volume that would accommodate all the drug in the body if conc. throughout were the same as in plasma”

41. Distribution Distribution: Also a matter of binding and sequestration Not just dilution Extensive plasma protein binding: Restriction to vascular component Low values of V E.g. Diclofenac and Warfarin (99% bound): V = 0.15 L Large V: Larger qty of drug in extravascular tissue Poisoning cases: Drugs with large V are not easily removed by haemodialysis

42. Distribution Alter V by Altering distribution of body water Altering membrane permeability Altering binding proteins Accumulation of metabolites displacing the drug from binding site Pathological states altering V Congestive heart failure Uremia Liver cirrhosis etc.

43. Redistribution Highly lipophilic drug initially distribute to highly perfused organs Brain, heart, kidneys etc. Later, less vascular but more bulky tissues take up the drug E.g. muscles, fat Plasma conc. falls, drug withdrawn from highly perfused sites Causes termination of action if site of action was a highly perfused one Anaesthetic action of Thiopentone sod terminated in a few minutes Relatively short hypnotic action (6-8 hr) by oral Diazepam/Nitrazepam Despite elimination half life of about 30 hr Greater the lipophilicity, faster is the redistribution

44. Penetration into Brain and CSF Capillary endothelium in brain has tight junction Lacks large paracellular spaces An investment of neural tissue covers the capillaries Together form “blood-brain barrier (BBB)” Similar blood-CSF barrier in coroid plexus Capillaries with tight junctions lined by coroidal epithelium Both are lipoidal; limit entry of non-lipophilic drugs Only lipophilic drugs penetrate and have action on CNS

45. Penetration into Brain and CSF Efflux transporters like P-gp and OATP also extrude many drugs Augment the barrier to potentially harmful xenobiotics Inflammation of meninges or brain increases permeability Some durgs may accumulate using transporters

46. Penetration into Brain and CSF Enzymatic BBB: MAO, cholinesterase etc in capillary walls or cells lining them Don’t allow catecholamines, 5-HT, Ach etc to enter brain in active form BBB is deficient in CTZ in medulla oblongata Even non-lipophilic drugs are emetic Exit from brain and CSF not dependent on lipophilicity Rather unrestricted Due to bulk flow of CSF back into blood through arachnoid villi Non-specific organic anion/cation transporters at choroid plexus

47. Passage Across Placenta Placental membranes are lipoidal Allow free passage of lipophilic drugs Restrict hydrophilic drugs Placental P-gp and other transporters also limit fetal exposure to drugs Placenta also metabolizes drugs May lower/modify the exposure of fetus to drug

48. Passage Across Placenta Restricted amounts of non-lipophilic drugs gain access to fetus Present in high concentration, or For long periods in maternal circulation Some influx transporters also operate Thus, it is an incomplete barrier Almost any drug taken by the mother can affect the fetus/newborn

49. Plasma Protein Binding Most drugs have affinity for plasma proteins, bind to them reversibly Acidic drugs generally bind to albumin Basic drugs to α 1 acid glycoprotein Binding to albumin quantitatively more important More abundant Extent depends on individual drug Increasing conc. of drug can saturate binding site Fractional binding may lower on giving large amounts of drugs Generally expressed % protein binding is for therapeutic doses

50. Clinical Implications of Plasma Protein Binding Highly plasma protein-bound drugs largely restricted to vascular compartment Tend to have smaller volumes of distribution Bound fraction is not available for action In equilibrium with free drug Dissociates when free drug con. is reduced due to elimination High protein binding: Generally longer-acting drug Bound fraction not available for excretion Unless actively extracted by liver or kidney tubules

51. Clinical Implications of Plasma Protein Binding Highly protein-bound drugs are not removed by haemodialysis Need special treatment in poisoning cases Generally expressed plasma conc. refers to bound and free drug Take into account when relating these to conc. active in vivo One drug can bind many sites on albumin Also more than one drugs can bind to same site

52. Clinical Implications of Plasma Protein Binding Drug bound with higher affinity displaces the one with lower affinity Increases conc. of its free form It will diffuse in tissues; also metabolized and excreted The new concentration is only marginally higher unless Displacement extends to tissue binding There is concurrent inhibition of metabolism/excretion Two highly bound drugs may not necessarily displace each other Sites may not overlap

53. Clinical Implications of Plasma Protein Binding Hypoalbuminemia: Binding may be reduced High concentrations may be attained Other diseases altering protein binding Uremia (reduced binding of Phenytoin) Pregnancy & inflammatory diseases (increased Propranolol binding) Increased acute phase reactant α 1 acid glycoprotein

54. Tissue Storage Drugs may accumulate in specific organs by active transport May also get bound to specific tissue constituents Drugs sequestered in tissues Unequally distributed Tend to have larger V Tend to have longer duration of action May exert local toxicity due to high concentration Tetracycline (bones and teeth), Chloroquine (retina) May also bind selectively to a cell organelle Tetracycline (mitochondria), Chloroquine (nuclei)

55. Metabolism

56. Biotransformation (Metabolism) Chemical alteration of drugs in body Needed to render non-polar compounds polar Not reabsorbed in renal tubules; excreted Most hydrophilic drugs are little biotransformed Excreted largely unchanged Metabolizing mechanisms protect from ingested toxins Also other environmental chemicals

57. Metabolism Main site: Liver Other sites: Kidney, intestine, lungs, and plasma Inactivation Drugs and their active metabolites rendered inactive/less active Alternative method, to excretion, of terminating the drug action Active metabolite from active drug Drugs partially converted to one or more active metabolite Effect is sum-total of that due to parent drug and active metabolite

58. Metabolism Activation of inactive drug Few drugs inactive as such; need conversion into active form These are called prodrugs Possible advantages of prodrug over active form Stability Bioavailability (or other desirable p’kinetic properties) Less side-effects or toxicity

59. Phase-I/Non-Synthetic Reactions Oxidation Addition of oxygen/-vely charged radical Or, removal of hydrogen/+vely charged radical Important: Hydroxylation, oxygenation at C/N/S, N/O-dealkylation etc Mostly carried out by a group of mono-oxygenases in liver Final step involves Cytochrome P-450 haemoprotein NADPH Cytochrome P-450 reductase Molecular O 2

60. Phase-I/Non-Synthetic Reactions Oxidation

61. Phase-I/Non-Synthetic Reactions Other Reactions Reduction Involves CYP enzymes working in opposite direction Alcohols, aldehydes, quinones are reduced Drugs primarily reduced: Chloramphenicol, Halothane, Warfarin Hydrolysis Cleavage of drug by taking up water molecule Amides and polypeptides hydrolyzed by amidases and peptidases Epoxide hyrolases detoxify epoxide metabolites generated by CYPs Drugs: Choline esters, Procaine, Aspirin, Indomethacin etc

62. Phase-I/Non-Synthetic Reactions Other Reactions Cyclization Formation of ring structures E.g. Cycloguanil from Proguanil Decyclization Opening up of ring structure E.g. Barbiturates, Phenytoin

63. Phase-II/Synthetic Reactions Conjugation with endogenous substrate Usually derived from carbohydrate or amino acids Forms polar/highly ionized organic acid Easily excreted through urine/bile Reactions have high energy requirements Generally faster than phase-I reactions

64. Phase-II/Synthetic Reactions Glucuronide Conjugation Most important reaction Conducted by a group of UDP-glucuronosyl transferases (UGTs) Compounds with OH/COOH groups easily conjugated with glucuronic acid Derived from glucose Examples: Aspirin, Paracetamol, Chloramphenicol, Diazepam etc Some endogenous substrates also use this pathway Bilirubin, steroid hormones, thyroxin

65. Phase-II/Synthetic Reactions Glucuronide Conjugation Increases molecular weight Favors excretion in bile Drug glucuronides excreted in bile can be hydrolyzed by gut bacteria Liberated drug is reabsorbed Undergoes same fate This enterohepatic cycling prolongs action

66. Phase-II/Synthetic Reactions Glutathione Conjugation Carried out by glutathione-S-transferase (GST) Forms a mercaptopurate Normally a minor pathway Inactivates highly reactive quinone/epoxide intermediates Formed during metabolism of drugs like Paracetamol Glutathione supply falls short if large amount of intermediates are formed In poisoning/after enzyme induction Toxic adducts with tissue constituents: Tissue damage

67. Phase-II/Synthetic Reactions Other Pathways Acetylation Compounds having NH 2 /hydrazine residues Conjugated with the help of acetyl Co-A E.g. Sulfonamides, Isoniazid, Dapsone etc Multiple genes control N-acetyl transferase Rate of acetylation shows genetic polymorphism Methylation Amines and phenols metabolized by methyl transferases E.g. Methyldopa, Adrenaline, Captopril etc Methionine and cysteine act as methyl donors

68. Phase-II/Synthetic Reactions Other Pathways Sulphate conjugation Phenolic compounds and steroids conjugated by sulfotransferases E.g. Chloramphenicol, Methyldopa, adrenal and sex steroids Glycine conjugation Salicylates, Nicotinic acid etc with COOH group Not a major pathway Ribonucleotide/nucleoside synthesis Important for activation of many purine and pyrimidine antimetabolites Used in cancer chemotherapy

69. Inhibition of Drug Metabolism Some drugs bind to haeme iron in CYP450 Inhibit the metabolism of many drugs Also of some endogenous substances: steroids, bilirubin etc A drug can competitively inhibit the metabolism of another one Not as common as one would expect Different drugs are substrates of different CYP450 isoenzymes A drug may be substrate and inhibitor of same isoenzyme A drug may be substrate to one isoenzyme, may inhibit different one

70. Inhibition of Drug Metabolism Majority of drugs are metabolized by non-saturation kinetics Enzyme is present in excess Clinically significant inhibition occurs if affinity for same isoenzyme Specifically if metabolized by saturation kinetics Inhibition occurs in a dose-dependent manner Can precipitate the toxicity of object drug Occurs by direct effect on enzyme Fast time course compared to enzyme induction

71. Microsomal Enzyme Induction Many drugs, insecticides, and carcinogens interact with DNA Increase the synthesis of microsomal enzyme proteins Particularly CYP450 and UGT Metabolism rate of inducing drug and/or some other drugs is enhanced Different drugs are relatively selective for certain CYO450 subfamilies Phenytoin, Phenobarbitone, Rifampin etc induce CYP3A Phenobarbitone and Rifampin also induce CYP2D6 and 2C8/9 Isoniazid and chronic alcohol consumption induce CYP2E1

72. Microsomal Enzyme Induction Increases metabolism of certain drugs but not others Inducers of CYP3A and CYP2D6 affect metabolism of large no. of drugs Induction involves microsomal enzymes in liver and other organs Increases the rate of metabolism by 2-4 fold Induction takes 4-14 days to reach peak Maintained till inducing agent is given Enzymes return to original level over 1-3 weeks

73. Consequences of Microsomal Enzyme Induction Decreased intensity and/or duration of action Increased intensity of action of drugs activated by metabolism Tolerance of drug induces its own metabolism Some endogenous substances are metabolized faster Precipitation of acute intermittent porphyria Increased prophyrin synthesis: Depress δ -aminolevulinic acid synthetase Intermittent inducer use may interfere with dose adjustment of another drug Drugs prescribed on a regular basis: Oral anticoagulants, antiepileptics Interference with chronic toxicity testing in animals

74. Possible Uses of Enzyme Induction Congenital non-haemolytic jaundice Due to inhibition of glucuronidation of bilirubin Phenobarbitone hastens clearance Cushing’s syndrome Phenytoin enhances degradation of adrenal steroids Chronic poisoning Faster metabolism of accumulated poisonous substance Liver disease

75. First-Pass Metabolism Metabolism of drug during its passage into systemic circulation All orally administered drugs undergo metabolizing enzymes In intestinal walls and liver Can be avoided by sublingual, transdermal, or parenteral route Limited metabolism can occur in skin and lungs Extend differs for different drugs Important determinant of oral bioavailability

76. First-Pass Metabolism A drug can also be excreted as such into bile Hepatic extraction ratio (ER Liver ) Fraction of absorbed drug prevented by liver from reaching circulation Both pre-systemic metabolism and direct excretion into bile decide ER Liver Drug with high first-pass given at higher dose Concentration of metabolites much higher Less safe than parenterals if metabolites contribute to adverse effects

77. Attributes of Drugs with High First-Pass Metabolism Oral dose considerably higher than sublingual/parenteral dose Marked individual variation in oral dose Differences in extent of first-pass Oral bioavailability apparently increased In severe liver disease If another drug competing in first-pass given concurrently

78. Excretion

79. Excretion Passage of a systemically absorbed drug out of the body Drugs and their metabolites are excreted in Urine Feces Exhaled air Saliva and sweat Milk

80. Renal Excretion Kidney excretes all water-soluble substances Net renal excretion = (Glomerular filtration + tubular secretion) – tubular reabsorption Glomerular filtration Pores of glomerular capillaries larger than usual All non-protein-bound drugs filtered Depends on plasma protein binding and renal blood flow GFR normally about 120 ml/min; declines after age of 50 Glomerular filtration declines parallelly

81. Renal Excretion Tubular Reabsorption Occurs by passive diffusion Depends on lipophilicity and ionization at urine pH Rate of excretion of ionized drugs parallels GFR E.g. aminoglycoside antibiotics, 4° ammonium compounds etc Changes in urinary pH affects reabsorption of ionized drugs Used for facilitating the elimination of drugs in poisoning E.g. Urine is alkalinized in barbiturate/salicylate poisoning

82. Renal Excretion Tubular Secretion Active transport of organic acids and bases Carried out by two sets of relatively non-specific transporters OATP and OCT Operate in proximal tubule Efflux transporters P-gp and MRP2 in luminal membrane of proximal tubule Active transport of drug reduces conc. of its free form in vessels Promotes dissociation of protein-bound drug Becomes available for active secretion

83. Renal Excretion Tubular Secretion Organic acid transport (through OATP) Penicillin, Uric acid, Indomethacin, Methotrexate etc Also for drug glucuronides and sulfates Organic base transport (through OCT) Thiazides, Triamterene, Quinine, Procainamide, Cimetidine etc Both are inherently bidirectional Drugs and their metabolites: Secretion into tubular lumen predominates Endogenous substances like uric acid are primarily reabsorbed Many drug interactions occur due to competition for tubular secretion

84. Kinetics of Elimination Elimination: Sum-total of metabolic inactivation and excretion Clearance (CL): Theoretical plasma volume from which drug is removed in unit time CL = Rate of elimination/plasma concentration

85. First-Order Kinetics of Elimination Rate of elimination is directly proportional to concentration CL remains constant A constant fraction of drug is eliminated in unit time Applies to majority of drugs that don’t saturate elimination process Transporters, enzymes etc. At high enough dose, elimination pathways will get saturated

86. Zero-Order Kinetics of Elimination Rate of elimination remains constant CL decreases with increase in concentration A constant amount of drug is eliminated per unit time Also called: Capacity-limited elimination Michaelis-Menten elimination