Factors affecting pharmacokinetic parameters

PG seminar on PK parameters

1. DETERMINANTS OF PHARMACOKINETIC PARAMETERS DR. JEFFREY PRADEEP RAJ, 1 ST YEAR PG DEPT. OF PHARMACOLOGY, SJMC 22 ND JUNE, 2015

2. TOPIC OVERVIEW Pharmacokinetics (PK) Definition PK Parameters Drug Absorption & Bioavailability Volume of Distribution Biotransformation of drugs (Metabolism) Drug elimination including Clearance & T ½ Summary References

3. PHARMACOKINETICS - DEFINITION Pharmacon – drug : kineticos – movement Study that deals with movement of drugs within the body “Process of absorption, distribution, metabolism (biotransformation) & elimination of drugs in the body” Absorption & distribution - rate of onset of action; Biotransformation & elimination - extent / duration of action

4. PHARMACOKINETIC PARAMETERS DEFINITION PARAMETER Absorption Movement of drug from site of administration into circulation Bioavailability (F) Distribution Pattern of scatter of specified amount of drug among various locations in the body Volume of Distribution ( Vd ) Metabolism Enzyme catalysed chemical transformation of drugs within living organism Elimination Excretion of drug metabolites outside the body Clearance (CL) Half Life (T ½)

5. ABSORPTION Drug Factors Patient factors Bioavailability

6. DRUG FACTORS (1/3) Concentration of Drug Lipid solubility ( E g . Fentanyl) Free movement across bio-membranes Crystal Form Amorphous Novobiocin better than crystalline form Spray dried Fenofibrate better than crys . FFB * * Yousaf AM et al. Effect of the preparation method on crystallinity, particle size, aqueous solubility and dissolution of different samples of the poorly water-soluble fenofibrate with HP-β-CD. Journal of Inclusion Phenomena and Macrocyclic Chemistry 2014; 81(3-4): 347-356

7. DRUG FACTORS (2/3 ) Dosage forms – Vehicle – water / oil Disintegration – solid form to break-up into individual particles Dissolution – disintegrated particle to dissolve in GI contents Eg : Albendazole + hydroxy propyl β cyclodextrin – better disintegration & dissolution* * MN Anjana et al. Solubility and bioavailability enhancement of albendazole by complexing with hydroxy propyl β cyclodextrin . Journal of Chemical & Pharmaceutical Research. 2015; 7(4): 1131-41

8. DRUG FACTORS (3/3) Particle Size Microfined griseofulvin better than griseofulvin Salt Form Salt of Weak acids – sod. Tolbutamide better than tolbutamide Water of hydration Anhydrous theophylline better than hydrous form

9. PATIENT FACTORS (1/3) Route of administration Parenteral Vs Enteral – Intranasal midazolam for seizures in children * Local metabolism Insulin not available orally - degraded by intestinal brush border enzyme peptidase Local Binding (in SC/IM Inj ) * Kälviäinen R. Intranasal therapies for acute seizures. Epilepsy & Behav (2015); doi:10.1016/j.yebeh.2015.04.027

10. PATIENT FACTORS ( 2/3) Local environment (P H , disease states) Tannic acid over burnt skin - liver necrosis Vascularity of absorbing surface Timolol eye drops - bradycardia while ointments did not; drops reached vascular nasal mucosa via Nasolacrimal duct * *Pratt NL et al. Association between Ophthalmic Timolol and Hospitalisation for Bradycardia. Journal of Ophthalmology 2015; doi:10.1155/2015/567387

11. PATIENT FACTORS (3/3) Drug – drug interactions Antacids forms complexes with tetracycline Vit. C favours iron absorption Area of absorbing surface Gentamicin - neurotoxicity in peritoneal wash* *Varghese JM et al Pharmacokinetics of Intraperitoneal Gentamicin in Peritoneal Dialysis Patients with Peritonitis (GIPD Study). Clin J Am Soc Nephrol . 2012 Aug 7; 7(8): 1249–1256.

12. Gastric emptying & GI motility Metoclopramide BA of Digoxin ; BA Paracetomol , Propantheline – opposite effect GI Diseases Coeliac disease - Fat malabsorption Amoxicillin absorption Cephalexin Food Phenytoin absorption better after food due to food induced bile secretion PATIENT FACTORS SPECIFIC TO ORAL ABSORPTION

13. BIOAVAILABILITY (F) Fraction of drug that reaches Site of action (or) Any biological fluid from which it gains access to site of action (or) Systemic circulation in the unchanged form Practical significance in low safety margin drugs (digoxin) / precise dosage control drugs (warfarin ) Bioavailability (F) % = AUC(ORAL ) / AUC (IV) X 100

14. DETERMINANTS OF BIOAVAILABILITY Absorption First Pass metabolism P Glycoprotein efflux pumps B iliary excretion

15. AREA UNDER THE CURVE (AUC) Gives extent of absorption Peak plasma conc. (C max ) Time to attain peak conc . ( T max ) C max & T max – indicate rate of Abs

16. DISTRIBUTION Volume of distribution Patient Factors (Perfusion, physiological barriers, diseased states, age & gender) Drug Factors (Plasma protein binding, Tissue affinity, P H & Ionisation, Lipid solubility / redistribution, Structure - activity relationship)

17. VOLUME OF DISTRIBUTION- Vd Apparent volume necessary to contain amount of drug homogenously at the same conc. found in plasma Vd = Q ty of drug administered / concentration of drug Lipid insoluble / highly protein bound drug– restricted to vascular compartment – low Vd Drugs sequestered in other tissues – large Vd

18. Vd MODELS One compartment model Body is single/homogenous Two compartment model Differential concentration among various organ systems

19. ORGAN PERFUSION RATE 2 compartments: ‘Central’: plasma and highly perfused tissue reservoirs Heart , brain, liver, kidney ‘Final’: slowly perfused organs Muscle, skin, fat, bone

20. PHYSIOLOGICAL BARRIERS TO DRUG DISTRIBUTION (1/2) Blood brain barrier Endothelial cells tightly joined Surrounded by less permeable glial cells Lipid soluble & nonionised drugs can enter Eg : L-dopa crosses BBB while dopa does not

21. PHYSIOLOGICAL BARRIERS TO DRUG DISTRIBUTION (2/2 ) Placental Barrier Allows lipid soluble non polar passive diffusion . High molecular weight dextran & Insulin cannot cross

22. DISEASED STATES & SPECIAL SITUATIONS Oedema – more fluid in trans-cellular compartment Sepsis – altered permeability to drugs following infection/inflammation of bio-membrane Pregnancy – added tissue and fluid volume ( ↑ Vd ) but ↓albumin – free drug conc. Unaltered: no dose change Obesity – excessive adipose tissue, ↑ Vd for lipophilic drugs like Diazepam

23. AGE & GENDER Total-body water differs with age and sex TBW of neonates ≈ 75–80% of body weight; Adult males 60%, Females 55% Body fat content Low i n children and men; ↓ Vd of lipophilic drugs Albumin is ↓ in new born & elderly; ↑ conc. of unbound drug that primarily bind to albumin

24. PLASMA PROTEIN BINDING Reversible binding - circulating drug reservoir Dynamic equilibrium: Free drug + Protein ↔ Drug-protein complex Not accessible to capillary diffusion, metabolism or excretion Extensive Protein binding – prolongs duration of action & availability, but need for larger dosing Albumin (warfarin, BZD), α 1 Acid glycoprotein (quinidine, CPZ), transcortin (glucocorticoids), Nucleoproteins (digoxin), α globulins (thyroxine), ϒ globulins (antigens)

25. TISSUE AFFINITY - OTHER RESERVOIRS (1/2 ) Tissues Iodine in thyroid Chloroquine in retina (nucleoproteins) CPZ in retinal pigment melanin Isoniacid in Brain Muscles Digoxin in heart & skeletal muscles Connective tissue Griseofulvin in keratin precursor cells

26. TISSUE AFFINITY - OTHER RESERVOIRS (2/2 ) Transcellular Chloramphenicol in aqueous humor Aminosugars in CSF Ampicillin in endolymph & joint fluid Imipramine in pleural fluid Fat Thiopentone , phenoxybenzamine Bones, teeth & Nails Tetracyclines , cisplatin

27. P H & IONISATION Weak bases / acids – unionised in basic / acidic P H respectively Unionised form crosses Bio-membranes Plasma P H is basic - Basic drugs unionised; diffuses into cell - large Vd But ICF is acidic - larger fraction is ionized & trapped intracellular

28. REDISTRIBUTION (LIPID SOLUBILITY) H ighly lipid soluble drugs get redistributed. First dose - short acting Repeated doses - long acting as drug saturates In snake bite, recurrent venom effect appear after initial stabilisation; Infusion of 5 ASV vials over 18 hours prevents this. Principle: ASV prevents redistribution of snake venom from bite site Monzavi SM, Dadpour B & Afshari R. Snakebite management in Iran: Devising a protocol . J Res Med Sci. 2014 Feb; 19(2): 153–163.

29. STRUCTURE ACTIVITY RELATIONSHIP Modifications in structure – profound effect on PK Phenytoin Fosphenytoin (addition of phosphate at N3 position) – better solubility in IV Fluoroquinolones - position 8 substituted with aryl cation – affinity to hypoxic cancer cells * * Peruccaa P, Savioa M, Cazzalinia O et al. Structure–activity relationship and role of oxygen in the potential antitumour activity of fluoroquinolones in human epithelial cancer cellsJ photochem Photobiol B  2014 Nov;140:57-68

30. METABOLISM Pathways Consequences Internal Factors determining metabolism External Factors

31. PATHWAYS OF DRUG MTABOLISM Phase I reactions Oxidation, reduction, hydroxylation Mostly microsomal involving CYP enzymes Results in active/inactive metabolite Phase II reactions Conjugation reactions (Glucuronide, N-acetyl, sulfate , amino acid, methyl, glutathione, ribosides ) Mostly non-microsomal except Glucuronidation Mostly inactive metabolites except Morphine glucuronide

32. HOFMANN ELIMINATION Inactivation of the drug by molecular rearrangement Spontaneous – no Enzymes Eg : A tracurium

33. CONSEQUENCES OF METABOLISM Formation of inactive metabolite Pentobarbitone to H ydroxypentobarbitone Formation of active metabolite from inactive drug (prodrug) Levodopa to dopamine Talampicillin to Ampicillin Formation of active metabolite from equally active metabolite Amitriptyline to Nortriptyline Codeine to Morphine

34. DETERMINANTS OF DRUG METABOLISM (1/2) INTERNAL FACTORS Age Neonates have low microsomal enzymes. Eg : Chloramphenicol causing Grey baby syndrome Elderly have reduced hepatic flow Race Chinese have high alcohol dehydrogenase, low Ald dehydrogenase Genetic variation Slow and fast acetylators of INH (Autosomal Recessive) Atypical pseudocholinesterase for SCh (Autosomal Recessive )

35. DETERMINANTS OF DRUG METABOLISM (2/2) EXTERNAL FACTORS Environment - Disease Liver diseases, Cardiac diseases ( blood flow to liver) & Hypothyroidism ( metabolism) Nutrition and Diet High proteins and poor carbohydrates – enhances metabolism Starvation – inhibits microsomal enzymes Drug-drug interaction (by stimulating/inhibiting SER development) Enzyme inducers – rifampicin, anticonvulsants Enzyme inhibitors – Valproate, cimetidine, erythromycin

36. ELIMINATION Clearance & Elimination kinetics Half Life Routes of elimination Renal Excretion & determinants Enterohepatic circulation Breast Milk

37. CLEARANCE (CL) Volume of biological fluid which is completely cleared of the drug per unit time CL of drug by organs is additive CL= CL renal + CL hepatic + CL other Kinetics of elimination can follow First order kinetics (Most drugs) Zero order kinetics (Alcohol) Mixed order kinetics (Phenytoin, tolbutamide , warfarin, digoxin)

38. FIRST ORDER KINETICS (1/2) Constant fraction of the drug is eliminated at fixed time interval 100g→50g →25g →12.5g Clearance remains constant for a drug at all dosing range CL = rate of elimination / C ml/min per Kg C = conc. Of drug

39. STEADY STATE CONCENTRATION At the 5 th half life, 97% of the drug is eliminated. If a fixed dose of drug is given at the end of every half life, by 5 t ½ plasma concentration reaches a plateau

40. ZERO ORDER KINETICS A constant quantity of drug is eliminated at fixed time interval 100g →50g →0g Clearance decreases with dose increments CL = Vm ( Km+C ) vm : maximal rate of elimination(mass/time) Km : conc. at which half maximal rate of elimination reached(mass/volume) C conc. of drug

41. MIXED ORDER KINETICS Michaelis – menten Kinetics / saturation kinetics First order at low doses Zero order at higher doses The metabolising enzymes get saturated at higher concentrations

42. ELIMINATION CONSTANT (k) Fraction of Vd cleared / unit time Slope of the straight line obtained by plotting log plasma concentration against time K = ln2/ t ½ (or) CL/ Vd

43. HALF LIFE (t ½ ) The time duration in which the plasma concentration of the drug falls by 50% Biological half life is the time duration in which the pharmacological effect falls by 50% T1/2 for one compartment model=0.693/K; k – elimination constant T1/2 for two compartment model=(0.693* Vss ) / CL; Vss is volume of drug at steady state.

44. ROUTES OF DRUG ELIMINATION A lveolar: GA gases, alcohol Faecal : Purgatives, MgSO4, Streptomycin, bacitracin, neomycin + bile excreted drugs Biliary: Quinine , Colchicine, vinblastine, corticosteroids, erythromycin, CPZ Renal: Metformin, aminoglycoside etc Saliva Hair Milk Sweat Skin

45. RENAL EXCRETION Glomerular filtration Active tubular secretion Passive tubular reabsorption

46. DETERMINANTS OF RENAL EXCRETION (1/2) Glomerular filtration Molecular size - upto 20kD filtered Protein binding - bound drug cannot be filtered Renal Blood flow Tubular secretion Drug P H : Two independent carrier systems for acidic and basic drugs Competitive inhibition among acidic drugs ( Probenecid inhibits tubular secretion of penicillin/amoxicillin – amox 3g oral + 500mg probenecid in Rx of syphilis * * Tanizaki R, Nishijima T, Aoki T et al . Clin Infect Dis. (2015) doi : 10.1093/cid/civ270

47. DETERMINANTS OF RENAL EXCRETION (2/2 ) Tubular reabsorption Lipid solubility- Quaternary ammonium salts and aminoglycosides are highly polar and are not reabsorbed Ionisation constant ( pKa ) & P H of urine Urine is acidic – weak acids are non-ionised and reabsorbed; vice-versa for weak bases (alkalinisation of urine – reabsorption of weak bases like Morphine) Strong acids and bases are ionised at all P H and are not reabsorbed Diseased states Chronic Renal Failure

48. DOSING ADJUSTMENT IN RENAL FAILURE RF affects at all 3 stages of renal excretion Also affects Renal metabolism & bioactivation Volume of distribution Non – renal clearance Protein binding Dosing adjustment based on creatinine clearance Cockcroft-Gault equation

49. BILIARY EXCRETION/ENTEROHEPATIC CIRCULATION Enterohepatic circulation prolongs drug action by Activation of prodrug ( digitoxin ) Reverses inactivation of inactivated metabolite of active drug ( glucoronides )

50. BREAST MILK EXCRETION Unwanted pharmacological action on a nursing infant Depends on PH partition principle Bases are generally avoided – morphine, chloramphenicol, tetracyclines , OCP

51. SUMMARY (1/2) S.NO PK Parameter Factors affecting 1 Absorption (Bioavailability) Drug related: concentration, dosage forms, lipid solubility, particle size, salt / crystal form, water of hydration. Patient related: GI contents, transit time, disease states, first pass metabolism, route, area & vascularity 2 Distribution (Volume of distribution) Patient Factors: Organ perfusion rate, Physiological barriers, Disease states, Age & Gender Drug Factors: Plasma protein binding, Tissue affinity, P H & Lipid solubility

52. SUMMARY (2/2) S.NO PK Parameter Factors affecting 3 Metabolism Internal Factors: Age, Race, Genetics External factors: diet, drug intake (induction/inhibition of microsomal enzymes) and diseased states 4 Elimination (Clearance & T ½) Glomerular factors: Molecular size, Protein binding/ unbound fraction & Blood flow to kidney Tubular factors: Urinary P H & ionization constant, Drug P H & lipid solubility Disease states: renal failure

53. REFERENCES Goodman L, Gilman A. Pharmacological basis of therapeutics. 12 th ed. Tata McGraw-Hill; 2012. p. 17-40 Rang HP, Dale MM, Ritter JM, Flower RJ. Pharmacology. 6 th ed. P. 98-130 Sharma HL, Sharma KK. Principles of Pharmacology. 1 st ed. Paras; 2007. p. 27-60 Tripathi KD. Essentials of Medical Pharmacology. 7 th ed. Jaypee ; 2013. p. 10-36 Katzung BG, Masters SB, Trevor AJ. Basic & Clinical Pharmacology. 12 th ed. Tata McGraw-Hill; 2012. p. 37-68 Journal articles as mentioned in each slide

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