QUANTITATIVE ASPECTS OF DRUG ACTION I (PHA 808)

(file:advpk1.phd)

COURSE HANDOUTSPRACTICE PROBLEMS

EQUATION SHEETS

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COURSE DESCRIPTION: Quantitative aspects of drug action I is a course designed to provide

the student with the advanced knowledge and skills necessary for

employing pharmacokinetic principles in the selection and evaluation

of drug therapy. Emphasis will be placed upon a complete understanding

of the basic and clinically applicable pharmacokinetic formulae

and the assumptions that are involved with their use. Aspects specifically

related to multiple dosing and accumulation ; drug protein binding and

non-linear pharmacokinetics will also be addressed.

CREDIT: 3 Semester hours

INSTRUCTOR: Dr. Martin D’Souza

REQUIRED TEXTBOOKS: Shargel, L and Yu, ABC (1999). Applied Biopharmaceutics and

Pharmaceitics, 4th Ed, Appleton and Lange, Norwalk

STUDENT EVALUATION: Problem Sets (10%); Exam I 40 %;Exam II 50%

GRADING SCALE: 90-100=A; 85-89.99=B+ ;80-84.99=B; 75-79.99=C+

70-74.99=C; 65-69.99=D; BELOW 65%= F

ATTENDANCE: Attendance is expected but no penalty is imposed for absences.

OVERALL OBJECTIVES OF THE COURSE

1 This course imparts a comprehension of the advanced skills necessary for employing pharmacokinetic principles. The knowledge gained from this course would be used to evaluate the pharmacokinetic parameters obtained in different patient populations.

2. The course is intended to provide the student with a working knowledge of the fate of a drug in the body. This course will also familiarize students with the relationships between binding, volume of distribution and half-life.

3. The course will also deals with aspects of multiple dosing and accumulation, drug protein binding and non-linear pharmacokinetics of drugs.

4. The pharmacokinetics of specific drugs will also be addressed.

COURSE COMPETENCIES:

1. To gain understanding and appreciation of the advanced concepts in pharmacokinetics

2. To be able to derive pharmacokinetic models and parameters from raw data

3. To be able to design and execute binding studies based on the type of drug of interest (i.e. acidic, basic, neutral,- high or low molecular weight)

4. To be able to design and execute pharmacokinetic studies to obtain kinetic data.

5. To be able to critically evaluate the pharmacokinetic literature.

6. To detect pathological problems and apply pharmacokinetic concepts to solve them.

COURSE TOPICS:

1. INTRODUCTION AND REVIEW (1hr)

-Review of mathematical fundamentals; -Determinants of drug activity

-Plasma, serum or whole blood concentrations as therapeutic guides

2. CONCEPTS (3hr)

Linear Pharmacokinetic Models

--Back projections and applications of stripping technique

--One, two and three compartment open model; --Blood flow rate limited models

3. PHARMACOKINETIC CALCULATIONS (3hr)

Estimation of AUC,Calculation of rates;Dosage regimen calculations;

dosage adjustment aided by blood level monitoring

4) Formal theories of the following dosage regimens:(6hr)

-multiple dosing and accumulation parameter

-calculations after oral dosing , iv bolus and iv infusions and combination of the iv and oral dosing.

5) Area-dose relationships in non-linear systems (3hr)

6) Parallel first order and capacity-limited kinetics (3hr)

7) Formal theories of drug binding, laboratory methods of determination of drug binding (5hr)

8) Factors affecting drug binding and non-linear protein binding (3hr)

9) PHARMACOKINETICS OF DRUGS IN SPECIFIC PATHOLOGICAL CONDITIONS: (6hrs)

- Sickle Cell Anemia,- Cancer , - Liver disease, - Renal failure

10) Assignments/Problem Sets

REFERENCE MATERIAL:(Multiple dosing and accumulation)

1. Wagner, J.G., Northam, J.I., Alway, C.D., and Carpenter, O.S.: Blood levels of drug at the equilibrium state after multiple dosing. Nature 207: 1301, 1965.

2. Gibaldi, M and Perrier, D.: Pharmacokinetics, Chapter 3 and Appendix E.

3. Kruger-Thiemer, E.: Formal theory of drug dosage regimens. I. J. Theoret. Bio. 13: 212, 1966.

4. Kruger-Thiemer, E.: Formal theory of drug dosage regimens. II. The exact plateau effect. J. Theoret. Biol. 23: 169, 1969.

5. Van Rossum, J.M.: Pharmacokinetics of accumulation. J. Pharm. Sci. 57: 2162, 1968.

6. Chiou, W.L.: Rapid compartment - and model- independent estimation of times required to attain various fractions of steady-state plasma level during multiple dosing of drugs obeying superposition principle and having various absorption or infusion kinetics. J. Pharm. Sci. 68: 1546, 1979.

7. DeVane, C.L., Wolin, R.E., and Jusko, W.J.: Pharmacokinetic basis for predicting steady-state serum drug concentrations of imipramine from single dose data. Commun. Psychopharmacol. 3: 353, 1979.

8. Smith, I.L. and Schentag, J.J.: Non-compartmental determination of the steady-state volume of distribution during multiple dosing. (Commun.) J. Pharm. Sci. 73: 281, 1984.

9. Chung, M.: Computation of model-independent pharmacokinetics parameters during multiple dosing. (Commun.) J. Pharm. Sci. 73: 570, 1984.

ZERO-ORDER INFUSIONS

1. Loo, JCK, and Riegelman, S: Assessment of Pharmacokinetics Constants from Postinfusion Blood Curves Obtained after IV Infusion, J. Pharm. Sci. 59: 53, 1970.

2. Wagner, J.G.: Scientific Commentary: Linear Pharmacokinetic Equations Allowing Direct Calculation of Many Needed Pharmacokinetic Parameters from the Coefficients and Exponents of Polyexnonential Equations Which Have Been Fitted to the Data, J. Pharmacokin. Biopharm. 4:443, 1976.

3. Wagner, J.G.: A Safe Method for Rapidly Achieving Plasma Concentration Plateaus, Clin. Pharmacol. Ther. 16: 691, 1974.

4. Kowarski, C.R., and Kowarski, A.A.: Simplified Method for Estimating Volume of Distribution at Steady State, J. Pharm. Sci. 69: 1222, 1980.

5. Gibaldi and Perrier: pp. 40-42, 422-423 (63-81).

REFERENCE MATERIAL: (Non-linear Pharmacokinetcs)

1. Gibaldi M and Perrier P: Chapter 7, pp. 271-318.

2. Perrier D, Ashley JJ and Levy G: Effect of product inhibition on kinetics of drug elimination. J Pharmacokin Biopharm 1: 231-242, 1973

3. Tsuchiya T and Levy G: Relationship between dose and plateau levels of drugs eliminated by parallel first order and capacity-limited kinetics. J Pharm Sci 61: 541-544 (1972)

4. Levy G: Pharmacokinetics at the interface between pharmacology and physiology, pp. 281-293 in PHARMACOKINETICS edited by Benet, Levy and Ferraiolo, Plenum 1984.

5. Chau NP: Area-dose relationships in nonlinear models. J Pharmacokin Biopharm 4: 537-551, 1976.

6. Martis L and Levy RH: Bioavailability calculations for drugs showing simultaneous first-order and capacity-limited elimination. J Pharmacokin Biopharm 1: 283-294, 1973.

7. McNamara PJ, Slattery JT, Gibaldi M and Levy G: Accumulation kinetics of drugs with nonlinear plasma protein and tissue binding characteristics. J Pharmacokin Biopharm 7: 397, 1979.

8. Wagner JG: Time to reach steady state and prediction of steady-state concentrations for drugs obeying Michaelis-Menten kinetics. J Pharmacokin Biopharm 6: 209-225, 1978.

Suggested Reading

1. Dowd JE and Riggs DS: A comparison of estimated Michaelis-Menten kinetic constants from various linear transformation. J Biol Chem 240: 863-869, 1965.

2. Hofstee BHJ: On the evaluation of the constants Vm and Km in enzyme reactions. Science 116: 329-331, 1952.

3. Eisenthal R and Cornish-Bowden A: The direct linear plot. A new graphical procedure for estimating enzyme kinetic parameters. Biochem J 139: 715-720, 1913.

4. Stoeckel K. McNamara PJ, McLean AJ, et al: Nonlinear pharmacokinetics of indocyanine green in the rabbit and rat. J Pharmacokin Biopharm 8: 483-493, 1980.

5. Conn RB, Sabo AJ, Landes D and Ho JYL: Inconstancy of renal clearance values with changing plasma concentrations. Nature 203: 143, 1964.

6. Jusko WJ and Levy G: Pharmacokinetic evidence for saturable renal tubular reabsorption of riboflavin. J Pharm Sci 59: 765, 1970.

REFERENCE MATERIAL: (Drug Protein Binding)

1. Goldstein, A., The Interaction of Drugs and Plasma Proteins, Pharmacol. Rev. 1: 102-165, (1949).

2. Meyer, M.C. and Guttman, D.E. The Binding of Drugs by Plasma Proteins, J. Pharm. Sci. 57: 895-918 (1969).

3. Anton, A.H. and Solomon, H.M., editors, Drug-Protein Binding, Annals N.Y. Acad. Sci. 226 1-362 (1973).

4. Jusko, W.J. and Gretch M., Plasma and Tissue Protein Binding of Drugs in Pharmacokinetics, Drug Metab. Rev. 5: 43-140 (1976).

5. Vallner, J.J., Binding of Drugs by Albumin and Plasma Protein, J. Pharm. Sci. 66: 447-465 (1977).

6. Birkett, D.J., Meffin, Peter J. and Wing, Lindon, M.H., Fundamentals of Clinical Pharmacology, 6: Plasma Protein Binding. Current Therapeutics: 89-98, August (1979).

Protein Properties

7. Settle, W., Hegeman, S. and Featherstone, R.M., The Nature of Drug-Protein Interaction, pp. 175-186, Chapter 8, in: Handbook of Experimental Pharmacology, Concepts in Biochemical Pharmacology, Brodie, B.B. and Gillette, J.R., editors, Springer-Verlag, New York (1971).

8. Litwack, G., Ketterer, B., and Arias, I.M., Ligandin: A hepatic protein which binds steroids, bilirubin, carcinogens and a number of exogenous organic anions, Nature 234: 466-467 (1971).

Measurement Methods

9. Chignell, C.F., Physical Methods for Studying Drug-Protein Binding, pp. 187-212, Chapter 9, in: Handbook of Experimental Pharmacology, Concepts in Biochemical Pharmacology, Brodie, B.B. and Gillette, J.R., editors, Springer-Verlag, New York, 1971.

10. Klotz, I.M., Physicochemical aspects of drug-protein interactions:a general

perspective, Annals N.Y. Acad. Sci. 226; 18-35 (1973).

11. Burke, C.W., Accurate Measurement of Steroid-protein binding by steady-state gel filtration, Biochem. Biophys. Acta. 176: 403- 413

(1969).

12. Shah, V.P., Wallace, S.M., and Reigelman, S., Microtrafiltration Technique for Drug-Protein Binding Determination in Plasma, J. Pharm. Sci. 63: 1364-1367 (1974).

13. Brodersen R., Competitive Binding of Bilirubin and Drugs to Human Serum Albumin Studied by Enzymatic Oxidation, J. Clin. Invest. 54: 1353-1364 (1974).

13a Whitlam J.B. and Brown, K.F.: Ultrafiltration in Serumprotein binding determination. J. Pharm. Sci. 70: 146-150 (1981).

14. Robertson, J.S. and Madsen, B.W., Kinetic Approach to Drug- Protein Binding, J. Pharm. Sci. 63: 234-239 (1974).

15. Hsu, P.L., Ma, J.K.H., Jun, H.W., and Luzzi, L.A., Structure Relationship for Binding of Sulfonamides and Penicillins to Bovine Serum Albumin by Fluorescence Probe Technique, J. Pharm. Sci. 63: 27-31 (1974).

Quantitation

16. Scatchard, G., The Attractions of Proteins for Small Molecules and Ions, Ann. N.Y. Acad. Sci. 51: 660-672 (1949).

17. Baulieu, E.E. and Raynaud, J.P., A "Proportion Graph" Method for Measuring Binding Systems, Europ. J. Biochem. 13: 239-304 (1970).

18. Rosenthal, H., A Graphic Method for the Determination and Presentation of Binding Parameters in a Complex System, Anal. Biochem. 20: 525-532 (1967).

19. Mais, R.F. Keresztes-Nagy, S., Zaroslinski, J.F., and Oester, Y.T., Interpretation of Protein-Drug Interaction through Fraction Bound and Relative Contribution of Secondary Sites, J.Pharm. Sci. 63: 1423-1427 (1974).

20. Perrin, J.H., Vallner, J.J., and Wold, S., an Unbiased Methods for Estimating Binding Parameters in a Non-Cooperative Binding Process, Biochem. Biophys. Acta 371: 482-490 (1974).

21. Priore, R.L. and Rosenthal, H.E., A Statistical Method for the Estimation of Binding Parameters in a Complex System, Anal. Biochem. 70: 231-240 (1976).

22. Yacobi, A., Lampan, T. and Levy G. Frequency Distribution of Free Warfarin and Free Phenytoin Fraction Values in Serum of Healthy Human Adults. Clin. Pharmacol. and Therap. 21: 283-286 (1977).

23. Chou, R.C. and Levy, G. Effects of Heparin or Salicylate Infusion on Serum Protein Binding and on Concentrations of Phenytoin in Serum, Brain and Cerebrospinal Fluid of Rats. J.Pharmacol. Exp. Therap. 219: 42-48 (1981).

Nonlinear Plasma Protein Binding

24. McNamara, P.J., Slattery, I.T., Gibaldi, M. and Levy G. Accumulation Kinetics of Drugs with Nonlinear Plasma Protein and Tissue Binding Characteristics. J. Pharmacokinetics and Biopharm. 7: 397-405 (1979).

25. McNamara, P.J. and Levy, G.L. Combined Effect of Concentration Dependent Protein Binding and Michaelis-Menton Elimination Kinetics on Time Course of Drug Concentrations in Plasma. Acta. Pharm. Fenn. 90: 99-106 (1981).

Structure-Activity

26. Hansch, C., Kiehs, K., and Lawrence, G.L., The Role of Substituents in the Hydrophobic Bonding of Phenols by Serum and Mitochondrial Proteins, J. Am. Chem. Soc. 87: 5770-5773 (1965).

27. Chien, Y.W. Lambert, and Lin, T.K., Linear Relationships between Plasma Binding and Lipophilicity of Disopyramide Derivative, J. Pharm. Sci. 64: 961-966 (1975).

Receptors

28. Mackerer, C.R., Kochman, R.L., Bierschenk, B.A., and Bremmer, S.S., the Binding of [3H] Diazepam to Rat Brain Homogenates, J. Pharmacol. Exp. Ther. 206: 205-2=413 (1978).

29. Roadbard, D., Mathematics of Hormone=Receptor Interaction I. Basic Principles, Adv. Exp. Med. Biol. 36: 289-326 (1973).

30. O'Brien, R.D., Editor, The Receptors, Vol. I. General Principles and Procedures, Plenum Press, New York, 1979.

31. Boeynaems, J.M. and Dumont, J.E. Outlines of Receptor Theory, Elsevier/North Holland Biomedical Press, Amsterdam, 1980.

Cooperativity

32. Gabler, E., Cooperative Concepts in Protein Binding Models - Problems of Cooperative Definition, Detection, Identification and Measuring, Die Pharmazie 32: 739-747 (1977).

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