1. Clearance Determinations Arthur G. Roberts

2. Routes of Elimination

3. Zero versus First-Order Elimination

4. Zero Order

5. First Order

6. 1 st Order Elimination rate of renal excretion = K renal * [Drug] rate of metabolism = K metabolism * [Drug] rate of biliary excretion = K biliary * [Drug] rate of other = K other * [Drug] Overall elimination = sum of all the rates Overall elimination = (K renal +K metabolism +K biliary +K other )*[Drug]

7. Clearance, Elimination and Excretion Clearance (Renal) (V/time, L/hr) Elimination (mass) (a.k.a. Extraction) Mechanisms for either – biotransformation (e.g. Cl int ) – excretion

8. Clearance efficiency for kidney or liver removal L/hour rapid or slow? – rel. large clearance and small volume distribution – rel. small clearance and large volume distribution rate of elimination (extraction) = Clearance * [Drug] plasma

9. Clearance Terms [Drug] in (mg/L) [Drug] out (mg/L) Q (L/h) Rate of Drug in = [Drug] in * Q Rate of Drug out = [Drug] out * Q Extraction Rate = ([Drug] in -[Drug] out ) * Q Extraction Ratio ([Drug] in -[Drug] out )/[Drug] in ) Clearance = E * Q Artery Vein

10. Example Rate Drug in, Rate Drug out, Extraction rate, extraction ratio, Clearance, Elimination Rate 1 L/(kg*hr) Kidneys Continuous IV infusion

11. Clearances

12. Clearance is additive sometimes Cl h

13. Elimination Rate Constant and Half Life Versus Clearance elimination rate = - K * Drug dose plasma = -Cl * [Drug] plasma K = Clearance (Cl)/Volume Distribution (Vd) T 1/2 = (ln 2)/K = (ln 2 * Vd)/Cl

14. Total Body Clearance [Drug] plasma

15. Renal Clearance Loop of Henle Proxima l Tubule Distal Tubule Collecting Duct

16. Glomerular Filtration Glomerulus Q at 1.2 L/min. or 72 L/hour prefer neutral 4-8 nm anionic albumin (7 nm) not filtered insulin (5 kD) filtered Normal glomerulus filtration rate 10% Q 7.2 L/ hour

17. Renal Clearance Neutral and small drug (< 8 nm) – not bound to plasma proteins Glomerular Filtration Rate (GFR) = Clearance (Cl GF ) – bound to plasma proteins fraction unbound (fu) * GFR = Cl GF Example: GFR = 9 L/hour fu = 30% CL GF = ?

18. Tubular Secretion

19. Tubular Reabsorption Lipophilicity pKa (acid and base forms)

20. Renal Clearance Renal Clearance (Cl r ) = Cl GF + Clearance from Tubular Secretion (Cl TS ) – Tubular Reabsorption (TR) Cl r = fu * GFR + Cl ts - TR

21. Renal Clearance Example Cl r = 1.8 L/hr GFR = 7.2 L/hr fraction bound = 80% What are the relative values for active tubular secretion (Cl TS ) and tubular reabsorption (TR)?

22. Renal Clearance [drug] plasma

23. Cl r Example PeriodVolume[Drug] urine Period[Drug] plasma 0-10.2150.50.240 1-30.18019.420.142 3-50.14012.840.071 5-100.43.57.50.021 Average Excretion Rate (mg/hour) = (Volume * [Drug] urine )/time 3 mg/hour = ( 0.2 *15)/1 mg/L hours L

24. Cl r Example PeriodAvg. Excretion Rate Period[Drug] plasma 0-130.50.240 1-31.74620.142 3-50.89640.071 5-100.2807.50.021 mg/L hours mg/hour slope = (3-0.280)/(0.240-0.21) slope = 2.72/0.219=12.4 L/hour=Cl r

25. Single-Point Determination of Renal Clearance Under Steady-State Conditions MeasurementAmountNormal Collection Period24 hours Volume Urine Collected 1.05 L Urinary Creatine Concentration 1140 mg/L400-3000 mg/L Plasma Creatine Concentration 10 mg/L6-12 mg/L 55 year old 65 kg female What is the average Cl r ?

26. Hepatic Clearance Mechanisms Biotransformation Excretion

27. Restrictive and Non-restrictive Clearance Non-restrictive E h > 0.7 Restrictive E h < 0.3

28. Non-Restrictive Hepatic Clearance: High E h

29. Restrictive Hepatic Clearance: Low E h

30. Blood and Plasma Hepatic Clearance plasma = protein and water

31. Example Cl plasma hepatic = 54 L /hr Q hb = 78 L/hr fu=1 ([drug] plasma /[drug] blood ) = 0.3 What is the extraction ratio? Does the drug undergo restrictive or non- restrictive clearance?

32. End of Clearance Determinations