1. MS STUDENTS: QUESTIONS TO KNOW SECTION

2. Flurbiprofen misspelled!

3. PROCESSES OF ELIMINATION AND CLEARANCE Lecture #9

4. CYP = Cytochrome P450 UDPG = UDP glucuronosyltransferase

5. Pathways of Drug Metabolism Oxidation and Reduction Conjugation Drugs 5

6. Phase I versus Phase II? 6 A B C D

7. Functions Good – Drug Clearance – Toxin Removal* – Homeostasis and Regulation* – Prodrug (inactive)  Active Drug* Bad -Reduced Efficacy -Increased Toxicity* 7

8. Functions: Toxin Removal bisphenol A Sulfonation Glucuronidation 8

9. Functions: Homeostasis and Regulation 9

10. Functions: Prodrug  Drug Antidepressant Antihistamine (Fura et al., 2004) Antihistamine Analgesic 10

11. Functions: Increased Toxicity Toxic Pathway 11

12. Abundance Contributions

13. Elimination Rate Example Midazolam: Dose = 7.5 mg CL = 28 L/hr V = 140 L C V =A/V = 7.5 mg/140 L = 0.05 mg/L Rate of Elimination (mg/hr) = 28 L/hr * 0.05 mg/L = 1.4 mg/hr

14. Extraction Rate and Extraction Ratio

15. =1 =E Extraction Rate Units = mg/hr

16. Fraction Remaining Q* Extraction Ratio Units = Unitless

17. Clearance Units= L/hr

18. Clearance Kidneys Liver Blood Flow (Q) Q H =Q R =1 L/hr/kg Q H =Q R =70 L/hr

19. Clearance Organ – Hepatic (liver) – Renal (kidneys) – Pulmonary (lungs) Process – renal/extrarenal – metabolic and excretory clearance Site of Measurement – reference fluid (blood vs. plasma clearance)

20. Additivity of Clearance Rate of Elimination Rate of Renal Excretion Rate of Hepatic Metabolism Rate of Biliary Excretion Rate of Other = + + + 25% 6%69% <1% Not Shown On Pie Chart CYP = cytochrome P450 UDP = UDP glucuronsyltransferases

21. Additivity of Clearance Rate of Elimination Rate of Renal Excretion Rate of Hepatic Metabolism Rate of Biliary Excretion Rate of Other = + + + 25% 6%69% <1%

22. Additivity of Clearance Rate of Elimination Rate of Renal Excretion Rate of Hepatic Metabolism Rate of Biliary Excretion Rate of Other = + + + 25% 6%69% <1% CVCV CVCV CVCV CVCV CVCV ~6%

23. Elimination Rate System Circulation Elimination rate CVCV CuCu C blood Assumption: Rapid equilibria between blood, plasma, bound and unbound.

24. Plasma versus Blood Clearance Binding of drugs to drug-binding proteins in the plasma. Binding to blood cells extensive. = 0.3 to 2.0

25. Plasma versus Blood Clearance DrugC V, µMC blood, µMC V /C blood Indomethacin24370.65 Loperamide1.030.911.13 Moxalaction7.50120.63 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949109/pdf/jcbfm2009200a.pdf DrugC V /C blood Amytriptyline1.13 Imipramine1.17 Nortriptyline1.67 Maprotiline2.23 Nomifensine1.21 Diazepam0.71 http://www.clinchem.org/content/26/11/1624.full.pdf

26. Plasma versus Blood Clearance Example Verapamil: Plasma/Blood ratio = 1.29 CL = 9 L/hr/kg V = 4.3 L/kg A = 0.142 mg/kg CL = 630 L/hr V= 301 L A= 10 mg Calculate C V C V =A/V=10 mg/301 L = 0.033 mg/L Calculate C blood Plasma/Blood ratio=1.29=(0.033 mg/L)/C blood C blood = 0.026 mg/L Calculate CL blood CL blood =CL*(C V /C blood ) CL blood =630 * 1.29 CL blood = 812.7 L/hr

27. Total (CL) versus Unbound Clearance (CL U ) CL = 0.26 L/hr/kg CL = 18.2 L/hr (70 kg) f u = 0.048 (i.e. ~95% bound) CL U =18.2/0.048 CL U =379 L/hr! tyrosine kinase inhibitor (anti-cancer)