1. ADVANCED PHARMACOKINETICS Prof. Dr. Henny Lucida, Apt

2. Topics Drug Distribution Drug Distribution Drug Elimination and Clearance Concepts Drug Elimination and Clearance Concepts Drug Metabolism Drug Metabolism Nonlinear Pharmacokinetics Nonlinear Pharmacokinetics

3. References Shargel, L and Yu, A, Applied Biopharmaceutics & Pharmacokinetics, 4 th ed., Appleton & Lange, 1999 Shargel, L and Yu, A, Applied Biopharmaceutics & Pharmacokinetics, 4 th ed., Appleton & Lange, 1999 Gibaldi, M and Perrier, D, Pharmacokinetics, 2 nd ed., Marcel Dekker, 1982 Gibaldi, M and Perrier, D, Pharmacokinetics, 2 nd ed., Marcel Dekker, 1982 Banker, G.S. and Rhodes, C.T., Modern Pharmaceutics, 3 rd ed., Marcel Dekker, 1996 Banker, G.S. and Rhodes, C.T., Modern Pharmaceutics, 3 rd ed., Marcel Dekker, 1996 Delgado,J.N. and Remers, W.A., Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, 9 th ed., J.B. Lippincott, 1991 Delgado,J.N. and Remers, W.A., Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, 9 th ed., J.B. Lippincott, 1991 Selected articles Selected articles

4. Drug Distribution Physiologic consideration Physiologic consideration Systemic circulation Oral adm GI tract Im or sc Tissue depots iv Receptors for desired effects drug Drug-drug metabolites DRUG Serum albumin drug Drug metab Drug-drug metabolites LIVER GI tract feces kidney Receptor for undesired effeect bile duct

5. Distribution pattern Onced absorbed, drugs reached systemic circulation and were distributed throughout the body, to receptor, other tissues (non receptor), eliminating organs, crossed the placenta, secreted in milk (ASI) and in fat tissues Body fluids (totally 42 L for 70 kg subject BW) 1. The vascular fluid (blood, + 5L) 2. The extracellular fluid (+ 15 L incl plasma 3L) 3. The intracellular fluid

6. Physicochemical factors Determined distr pattern of drugs, incl: MW (low MW & water soluble drugs were uniformly distributed throughout the bodywater) MW (low MW & water soluble drugs were uniformly distributed throughout the bodywater) Solubility Solubility pKa (only molecular form passed the physiological membrane) pKa (only molecular form passed the physiological membrane) Partition coefficient (lipid soluble drugs tend to accumulate in fat tissues) Partition coefficient (lipid soluble drugs tend to accumulate in fat tissues) Affinity to plasma protein (high affinity drugs, stay largely within the vascular system) Affinity to plasma protein (high affinity drugs, stay largely within the vascular system)

7. Physiological factors Membrane permeability (highly permeable: renal and hepatic capillaries, impermeable: brain capillaries; blood- brain barrier) Membrane permeability (highly permeable: renal and hepatic capillaries, impermeable: brain capillaries; blood- brain barrier) Blood perfusion rate (kidneys>liver>heart> brain>fat>muscle> skin>bone) Blood perfusion rate (kidneys>liver>heart> brain>fat>muscle> skin>bone) Exp: thiopental gets into the brain faster than muscle, whereas penicillin was viceversa Thiopental is partly ionized and passes both organs easily. Perfusion limits the transport thus it can transfer to the brain more quickly. Penicillin, being quite polar and thus slowly permeable. Permeability limits transfer thus it gets muscle easily (brain is impermeable)

8. Distribution process Passive diffusion (Fick’s law of diffusion) Passive diffusion (Fick’s law of diffusion) Hydrostatic pressure (a pressure gradient between the arterial end of the capillaries entering the tissue and the venous capillaries leaving the tissue).Responsible for penetration of water-soluble drugs. Hydrostatic pressure (a pressure gradient between the arterial end of the capillaries entering the tissue and the venous capillaries leaving the tissue).Responsible for penetration of water-soluble drugs.

9. Perfusion or flow limited distr. If a drug difuses rapidly across the membrane so that blood flow is the rate limiting step (slower) If a drug difuses rapidly across the membrane so that blood flow is the rate limiting step (slower) exp: thiopental, transport to the brain

10. Diffusion or permeability limited distr. If drug distribution is limited by the slow diffusion of drug across the membrane in the tissue If drug distribution is limited by the slow diffusion of drug across the membrane in the tissue exp: penicillin, diffused very slowly due to its polarity

11. Two compartment open model Tissue compartment Central compartment (plasma) k 12 k 21 Absorption k 10 Elimination Distribution

12. Apparent volume of distribution Lack of true volume characteristics (due to unknown tissue volume). Lack of true volume characteristics (due to unknown tissue volume). Vd app of some drugs exceed total body water (see Table 1). Defined as the hypothetical volume relating the drug plasma concentration to the weight of drug in the body Defined as the hypothetical volume relating the drug plasma concentration to the weight of drug in the body A useful indicator of the type of distribution pattern, exp: V= 3-5 L (in an adult) the drug remain largely within the vascular system; V= 30 – 50 L the drug is distributed throughout the body water; V >>> total body water drugs are concentrated in one or more tissues (highly lipid soluble drugs distribute into fat tissue, digoxin is extensively bound by myocard protein) A useful indicator of the type of distribution pattern, exp: V= 3-5 L (in an adult) the drug remain largely within the vascular system; V= 30 – 50 L the drug is distributed throughout the body water; V >>> total body water drugs are concentrated in one or more tissues (highly lipid soluble drugs distribute into fat tissue, digoxin is extensively bound by myocard protein)

13. Tabel 1. Apparent Vd of some drugs DrugLiters/kg Liter/70 kg Chloroquine 94 – 250 6600 – 17500 Nortriptyline211500 Digoxin7500 Lidocaine1.7120 Theophylline0.535 Tolbutamide0.118

14. Basic equations C p = D B /V d C p = D B /V d Distrib. Half life: Distrib. Half life: Q=blood flow to the organ,V=volume of the organ & R=ratio of drug conc in tissue to conc in blood T 1/2 elimination Vd T 1/2 elimination Vd CL = k V d T 1/2 = 0.693 V d /CL

15. Calculation of Vd app. V app = D B /C p V app = D B /C p D B = V p C p + V t C t D B = V p C p + V t C t V app = V p + V t [f u /f ut ], if f u and f ut are both unity, then V app = V p + V t [f u /f ut ], if f u and f ut are both unity, then D B /C p = V p + V t D B /C p = V p + V t Estimation of V app Estimation of V app

16. Protein Binding Major proteins to which dugs bind in plasma: albumin (acidic drugs),  1-acid glycoprotein (basic drugs), lipoproteins Significance: only free drug is able to cross membrane, the bound drug could serve as reservation only free drug is able to cross membrane, the bound drug could serve as reservation Possibility of drug interaction by binding displacement Possibility of drug interaction by binding displacement Free drug conc was also determined by patophysiological conditions relating with changes in the amount of protein in the body Free drug conc was also determined by patophysiological conditions relating with changes in the amount of protein in the body

17. Drug-Protein Binding Reversible Reversible hydrogen or van der walls bound (weak) Irreversible Irreversible cause toxicity such as hepatotoxicity due to binding of acetaminophen to liver protein

18. Effect of reversible protein binding on drug distribution & elimination Tissues Plasma Kidney Liver Drug-Receptor Receptor + Drug Protein + Drug Drug-Protein Carrier+Drug Drug-Carrier Drug+Enzymes Metabolites Clinical response Excretion In urine Active renal secretion Excretion In urine Excretion In bile

19. Table: Influence of protein binding on t1/2 & CL R Drug % Bound T1/2 (hr) CL R (mL/min/1.73m 2 ) Ceftriaxone968.010 Cefoperazone901.819 Cefotetan853.328 Ceforanide813.044 Cefazolin701.756 Moxalactam522.364 Cefsulodin261.590 Ceftazidime221.985 Cephaloridine211.5125

20. Methods for studying drug-protein binding Equilibrium dialysis Equilibrium dialysis Dynamic dialysis Dynamic dialysis Ultrafiltration Ultrafiltration Gel Chromatography Gel Chromatography Spectrophotometry Spectrophotometry Electrophoresis Electrophoresis Circulatory dichroism Circulatory dichroism

21. Clinical Significance Factors that decrease plasma protein conc: Liver disease: decrease protein synthesis Liver disease: decrease protein synthesis Trauma, surgery: increased protein catabolism Trauma, surgery: increased protein catabolism Burns: Distribution of albumin into extravascular space Burns: Distribution of albumin into extravascular space Renal disease: Excessive elimination of protein Renal disease: Excessive elimination of protein