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COMPARTMENTAL ANALYSIS OF DRUG DISTRIBUTION

COMPARTMENTAL ANALYSIS OF DRUG DISTRIBUTION. Arthur J. Atkinson, Jr., M.D. Senior Advisor in Clinical Pharmacology Clinical Center, NIH. DRUG DISTRIBUTION. THE POST-ABSORPTIVE TRANSFER OF DRUG FROM ONE LOCATION IN THE BODY TO ANOTHER. GOALS OF DRUG DISTRIBUTION LECTURE.

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COMPARTMENTAL ANALYSIS OF DRUG DISTRIBUTION

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  1. COMPARTMENTAL ANALYSISOF DRUG DISTRIBUTION Arthur J. Atkinson, Jr., M.D. Senior Advisor in Clinical Pharmacology Clinical Center, NIH

  2. DRUG DISTRIBUTION THE POST-ABSORPTIVE TRANSFER OF DRUG FROM ONE LOCATION IN THE BODY TO ANOTHER

  3. GOALS OF DRUG DISTRIBUTION LECTURE • SIGNIFICANCE OF DRUG DISTRIBUTION • VOLUMES • PHYSIOLOGIC BASIS OF MULTI- • COMPARTMENT PHARMACOKINETIC • MODELS • CLINICAL IMPLICATIONS OF DRUG • DISTRIBUTION KINETICS

  4. DIGOXIN DISTRIBUTION VOLUME

  5. BODY FLUID SPACES (CONVENTIONAL VIEW) cell membranes

  6. DRUGS WITH Vd CORRESPONDING TO PHYSIOLOGICAL FLUID SPACES INTRAVASCULAR SPACE: NONE EXTRACELLULAR FLUID SPACE: INULIN PROTEINS & OTHER MACROMOLECULES NEUROMUSCULAR BLOCKING DRUGS (N+) AMINOGLYCOSIDE ANTIBIOTICS (initially) TOTAL BODY WATER: UREA CAFFEINE ETHYL ALCOHOL ANTIPYRINE (some protein binding)

  7. DISTRIBUTION VOLUME OF REPRESENTATIVE MACROMOLECULES

  8. FACTORS AFFECTING VdESTIMATESOF MOST DRUGS BINDING TO PLASMA PROTEINS: THYROXINE THEOPHYLLINE TISSUE BINDING (PARTITIONING): DIGOXIN (Na+ - K+ ATPase) LIPOPHILIC COMPOUNDS

  9. PHYSIOLOGICAL SPACES FOR DRUG DISTRIBUTION CELL MEMBRANES ICF ECF ELIMINATION

  10. EFFECT OF BINDING CHANGES ON Vd OF THYROXINE & THEOPHYLLINE* fu is the “free fraction”, the fraction of drug in plasma that is not bound to plasma proteins. * Atkinson AJ Jr, et al. Trends Pharmacol Sci 1991;12:96-101.

  11. IMPACT OF PROTEIN BINDING ON THYROXINE DISTRIBUTION VOLUME* fu=0.03% Vd = VECF * From Larsen PR, Atkinson AJ Jr, et al. J Clin Invest 1970;49:1266-79.

  12. IMPACT OF PROTEIN BINDING ON THEOPHYLLINE DISTRIBUTION VOLUME* fu=60% Vd = VECF + fuVICF * From Atkinson AJ Jr, et al. Trends Pharmacol Sci 1991;12:96-101.

  13. BASIS FOR INCREASED THEOPHYLLINE Vd IN PREGNANCY * From Frederiksen MC, et al. Clin Pharmacol Ther 1986;40;321-8.

  14. EFFECT OF BINDING CHANGES ON VdOF MOST DRUGS* Ф is the ratio of tissue/plasma drug concentration. * Atkinson AJ Jr, et al. Trends Pharmacol Sci 1991;12:96-101.

  15. VD (L/kg) fU Ф OCTANOL/WATER PARTITION COEF. = 10 – 100* PHENYTOIN 0.64 0.08 12 DIAZEPAM 1.10 0.013 185 OCTANOL/WATER PARTITION COEF. = 100 - >1000* PROPRANOLOL 4.30 0.13 82 NORTRIPTYLINE 18.0 0.08 572 *measured at pH 7 LIPID SOLUBILITY & 

  16. APPARENT Vd OF DIGOXIN Φrepresents binding to Na+-K+ ATPase.

  17. mµC/gm HOURS TISSUE VS. PLASMA DIGOXIN LEVELS

  18. GOALS OF DRUG DISTRIBUTION LECTURE • SIGNIFICANCE OF DRUG DISTRIBUTION • VOLUMES • PHYSIOLOGIC BASIS OF MULTI- • COMPARTMENT PHARMACOKINETIC • MODELS • CLINICAL IMPLICATIONS OF DRUG • DISTRIBUTION KINETICS

  19. BASIC PHARMACOKINETIC MODELS* * From Atkinson AJ Jr, et al. Trends Pharmacol Sci 1991;12:96-101.

  20. MONES BERMAN

  21. MATHEMATICAL VS. PHYSICAL MODELS* MATHEMATICAL MODEL: FUNCTIONS OR DIFFERENTIAL EQUATIONS ARE EMPLOYED WITHOUT REGARD TO ANY MECHANISTIC ASPECTS OF THE SYSTEM PHYSICAL MODEL: IMPLIES CERTAIN MECHANISMS OR ENTITIES THAT HAVE PHYSIOLOGICAL, BIOCHEMICAL OR PHYSICAL SIGNIFICANCE * Berman M: The formulation and testing of models. Ann NY Acad Sci 1963;108:182-94

  22. FIRST MULTICOMPARTMENTAL ANALYSIS OF DRUG DISTRIBUTION* * FromTeorell T. Arch Intern Pharmacodyn 1937;57:205-25.

  23. IS CENTRAL COMPARTMENT INTRAVASCULAR SPACE? • USUALLY NOT IDENTIFIED AS SUCH • UNLESS DRUG GIVEN RAPIDLY IV • NEED TO CONSIDER: • - IF DISTRIBUTION LIMITED TO ECF, • COMPARE VC WITH PLASMA VOLUME. • - IF LARGER DISTRIBUTION VOLUME, • COMPARE VC WITH BLOOD VOLUME • ACCOUNTING FOR RBC/ PLASMA.

  24. IF VC IS BASED ON PLASMA CONCENTRATION MEASUREMENTS RBC/P = red cell/plasma partition ratio Hct = hematocrit

  25. ANALYSIS OF PA & NAPA CENTRAL COMPARTMENT VOLUMES* * From Stec GP, Atkinson AJ Jr. J Pharmacokinet Biopharm 1981;9:167-80.

  26. ANALYSIS OF EXPERIMENTAL DATA HOW MANY COMPARTMENTS? DESPITE AVAILABILITY OF COMPUTER PROGRAMS FOR PK ANALYSIS, STILL NEED TO MAKE INITIAL ESTIMATES.

  27. TECHNIQUE OF CURVE PEELING A’ β α

  28. Dose k21 Central V1 Periph. V2 k01 k12 COMPARTMENTAL ANALYSIS DATA EQUATION: C = A´e-αt+ B´e-βt MODEL EQUATION: dX1/dt = -(k0 + k12)X1 + k21X2

  29. Dose Central V1 Periph. V2 CLI CLE TWO-COMPARTMENT MODEL Vd(ss) = V1 + V2

  30. 3 DISTRIBUTION VOLUMES

  31. Dose Central V1 Periph. V2 CLI CLE k01 TWO-COMPARTMENT MODEL CLE = k01V1

  32. INTERCOMPARTMENTAL CLEARANCE* A VOLUME-INDEPENDENT PARAMETER CHARACTERIZING THE RATE OF ANALYTE TRANSFER BETWEEN COMPARTMENTS OF A KINETIC MODEL * FromSaperstein et al. Am J Physiol 1955;181:330-6.

  33. Dose k21 Central V1 Periph. V2 CLI k12 CLE TWO-COMPARTMENT MODEL CLI = k21 V1 = k12 V2

  34. [PROCAINAMIDE] (μg/mL) HOURS 3-COMPARTMENT MODEL OF PA PHARMACOKINETICS

  35. CATENARY 3-COMPARTMENT MODEL cell membranes

  36. [INULIN] (mg/dL) AFTER INFUSION AFTER BOLUS MINUTES ANALYSIS OF INULIN KINETICS WITH A 2-COMPARTMENT MODEL* * Gaudino M. Proc Soc Exper Biol Med 1949;70:672-4.

  37. CELL MEMBRANES 3-COMPARTMENT MODEL OF INULIN KINETICS EXTRACELLULAR FLUID VF Dose CLF VC CLS VS CLE

  38. BASIS FOR KINETIC HETEROGENETIY

  39. ENDOTHELIAL FENESTRAE IN HEPATIC SINUSOIDS

  40. INTERENDOTHELIAL CELL JUNCTION IN CONTINUOUS CAPILLARY

  41. PK-PD STUDY OF INSULIN ENHANCEMENT OF SKELETAL MUSCLE GLUCOSE UPTAKE* * From Sherwin RS, et al. J Clin Invest 1974;53:1481-92.

  42. UREA-15N2 KINETICS INA NORMAL SUBJECT

  43. MULTICOMPARTMENTAL MODEL OF INULIN AND UREA KINETICS* * From Atkinson AJ Jr, et al. Trends Pharmacol Sci 1991;12:96-101.

  44. ROLE OF TRANSCAPILLARY EXCHANGE THE CENTRAL COMPARTMENT FOR BOTH UREA AND INULIN IS INTRAVASCULAR SPACE. THEREFORE, TRANSCAPILLARY EXCHANGE IS THE RATE-LIMITING STEP IN THE DISTRIBUTION OF BOTH COMPOUNDS TO THE PERIPHERAL COMPARTMENTS OF THE MAMMILLARY 3-COMPARTMENT MODEL.

  45. RENKIN EQUATION* Q = capillary blood flow P = capillary permeability coefficient-surface area product (sometimes denoted P•S). * From Renkin EM.Am J Physiol 1953;183:125-36.

  46. Dose VC CLE 3-COMPARTMENT MODEL VF CLF = QF (1 – e PF/QF) CLS = QS (1 – e PS/QS) VS

  47. SUBJECT 1 INULIN UREA SIMULTANEOUS ANALYSIS OF INULIN AND UREA-15N2 KINETICS How does QF + QS compare with C.O.?

  48. 3 UNKNOWNS: 3 EQUATIONS: FOR EACH COMPARTMENT U = urea; I = inulin D = free water diffusion coefficient

  49. CARDIAC OUTPUT AND COMPARTMENTAL BLOOD FLOWS* * From Odeh YK, et al. Clin Pharmacol Ther 1993;53;419-25.

  50. MECHANISMS OF TRANSCAPILLARYEXCHANGE DIFFUSIVE TRANSFER: M.W. < 6,000 DALTONS CONVECTIVE TRANSFER: M.W. > 50,000 DALTONS

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