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Upcoming Exams

Upcoming Exams. Tuesday March 11, 4:30-7:30, Rm 257 Remediation/Make-up Exam 1 Thursday March 13, 4:30-7:30, Rm 257 Remediation/Make-up Exam 2 Tuesday, March 18, 9:30-11:18, Rms 103 & 107 Exam 3. Dosing Regimen Individualization. Drug Interactions Absorption Distribution Elimination.

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Upcoming Exams

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  1. Upcoming Exams • Tuesday March 11, 4:30-7:30, Rm 257 • Remediation/Make-up Exam 1 • Thursday March 13, 4:30-7:30, Rm 257 • Remediation/Make-up Exam 2 • Tuesday, March 18, 9:30-11:18, Rms 103 & 107 • Exam 3

  2. Dosing Regimen Individualization Drug Interactions Absorption Distribution Elimination

  3. Drug Interactions • Absorption: ka and FAB • Binding • Motility • Distribution: V • Displacement - fup • Elimination: CL • Displacement – fup • Metabolism induction, inhibition – CLint,u • Hemodynamic – QH • pHurine

  4. Introductory Points • Interactions are graded. • Many are too small to affect therapy. • Therapeutic Drug Interaction: when there is diminished therapeutic efficacy. • Detection (observation) most likely when interacting drug is initiated or withdrawn. • Usually unidirectional, rarely bi-directional.

  5. Time Course Manifestation of an interaction (e.g., elevated or depressed plasma concentration of drug) may require a relatively long time. 2nd Drug CLint,u via induction Css,av 1 week subtherapeutic Time

  6. Physical Interactions Physiological Change QH GI Motility fup Altered primary PK ka F V CLR CLH Competition for receptors E Cp log Cp Time Pharmacokinetic vs. Pharmacodynamic

  7. Absorption: ka & FAB Binding: adsorbent such as kaolin-pectin mixture or bile-acid sequesterants may reduce both ka and FAB. MJ Malloy et al. Int. J. Clin. Pharmacol. Therap. 35:250, 1997; 32:286, 1994.

  8. Valproic Acid EHC Sulindac

  9. Mean  SD of 6 subjects; *significantly different from control and cholestipol (p < 0.05 ) M.A. Al-Meshal, et al. Biopharm. & Drug Disposition 15:463-471,1994.

  10. S.R. Al-Balla et al. Int. J. Clin. Pharmacol. Therap. 32:441-445,1994. Discrepancy in Tmax and Cmax values between table and figure result from fig. showing average plasma concentrations and table showing the average of the individual Tmax and Cmax values.

  11. t50% = Vo(0.1797 - 0.167e-K) min mL K = caloric density, Kcal/mL GI Motility 3 hr Transit       Release: disintegration, dissolution Primary site of absorption is the small intestine. Sm. Intestinal Transit Time is about 3 hr. stomach Permeation

  12. Gastric Emptying Rate PEG 4000 Important determinant of rate of absorption, particularly when the drug is rapidly absorbed from the small intestine. sulfanilamide ME Brady et al. J. Pharm. Sci. 66:366-370,1977.

  13. t50% = Vo(0.1797 - 0.167e-K) min mL K = caloric density, Kcal/mL Gastric Emptying Rate • Examples: • Glass of water. Vo = 350 mL, K = 0, t50% = 4.5 min. • Beverage, 200 Cal. Vo = 350 mL, K = 0.571 Kcal per mL, t50% = 30 min. • Meal, 800 Cal. Vo = 600 mL, K = 1.33 Kcal/mL, t50% = 108 min.

  14. Gastric Emptying Rate

  15. Effects of Reduced Motility on Drug Absorption

  16. Poorly Absorbed, transporter; riboflavin Well Absorbed; acetaminophen propantheline

  17. Poorly absorbed due to slow dissolution; digoxin Tablets Solution

  18. Impacts: What to do with DR? ka has no effect on Css; peaks and troughs are modulated. No change in DR necessary. FAB causes proportional changes in Css and proportional change in DR is required.

  19. DISPLACEMENT: reduction in drug binding • Mechanisms • Competition for same site with another drug or substance, the displacer • Allosteric mechanism; second drug induces conformation change in binding site. May result in increased as well as decreased binding. • For competitive displacement to cause a therapeutic drug interaction: • displaced drug must be highly bound (>95%). • [displacer] > [binding sites]

  20. Binding Sites: macromolecules • Albumin • Involved in binding of most bound drugs. • 6 major binding sites per molecule. • High plasma concentration: 600 M • Acidic drugs are prominently bound, two sites:

  21. Binding Sites: macromolecules • 1 acid glycoprotein • 1 binding site per molecule. • Low plasma concentration: 10-40 M • Basic drugs are prominently bound • Acute stress protein; concentration in plasma can rise markedly after surgery, burn, etc. Immunoglobulins Play no role in drug binding.

  22. Binding Sites: formed elements • Plasma lipoproteins: bind fat-soluble drugs • chylomicrons, VLDL, LDL, HDL • elevated after a meal

  23. Binding Sites: formed elements • Leukocytes and Platelets • high affinity for some drugs but low capacity; i.e., easily saturable.

  24. Binding Sites: formed elements • Erythrocytes • Three drug binding components • hemoglobin: binds phenothiazines, pentobarbital, phenytoin • carbonic anhydrase: binds acetazolamide, and chlorthalidone • membrane: binds chlorpromazine and imipramine

  25. Concentration dependence

  26. Displacement - fup • Acute Events: • Cp,total drops rapidly and extensively. • Cp,unbound increases rapidly but modestly. • Chronic (Plateau) Events: depends on effect on CL • CLH - Depends on E and route of administration • all E p.o. and low-E parenteral: no effect • high-E parenteral: Css,u directly proportional to fup • CLR – directly proportional to fup (except high-E ATS)

  27. Diminished Unbound CL G.K. Dresser, et al. Clinical Pharmacok. 38:41-57, 2000.

  28. When there is first-pass hepatic elimination When elimination involves primarily one enzyme and that enzyme is also responsible for extensive first-pass elimination, very large effects result from inhibition. P-gp inhibition may also be involved.

  29. High First-Pass / CYP3A4

  30. Example: Midazolam p.o.FFP = 50% Backman JT et al. Eur. J. Clinical Pharmacology 54:53-58 (1998)

  31. itra D-11 itra D-15 control rif D-37 rif D-33 itra D-11 itra D-15 control

  32. Midazolam PK Parameters

  33. Other Examples

  34. Other Mechanisms  CLint,u •  Q to clearing organ for high E •  active tubular secretion •  pHurine for weak acid, HA •  pHurine for a weak base, B

  35. Elevated Unbound Clearance • Induction Mechanisms for Drug Metabolism Enzymes • Enzyme stabilization: ethanol and CYP2E1. Enzyme is destabilized when substrate binds to cyp. When ethanol binds to 2E1, the 2E1 is stabilized, which over time results in an increased amount of 2E1. Initially activity is reduced due to enzyme being occupied (acute effect). After continued exposure, amount of enzyme increases but occupation continues. Activity appears to be similar to baseline (pre-ethanol exposure). When inducer is withdrawn, occupation ceases and activity appears to be elevated. • Increased Expression

  36. Enzymes subject to induction U. Fuhr. Clinical Pharmacokinetics 38:493-504, 2000.

  37. Dr. Mungall Therapeutic Drug Monitoring – next three classes. Lectures are soon available on WebCT site – those taking the early final exam will need to take Dr. Mungall’s third class from the web. He will include that material on the early exam.

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