1. Clearance: basic concept (in vitro) Update OCT 2010

2. Clearance: definition What is a definition Formal: –rate of drug elimination scaled by plasma concentration Operational –Volume of the plasma totally cleared by time unit

3. Operational definition Is the one that expresses what is observed, without regarding how it may be interpreted

4. Rate of elimination driving concentration Clearance = = dx /dt driving concentration Amount/Time concentration mass x T -1 mass x V -1 = V x T -1 Clearance: definition

5. Clearance : from in vitro to in vivo

6. cell dx/dt Driving concentration = constant analyte Clearance = = Volume of the solution totally cleared by time unit dx/dt Cst intrinsic = operational definition In vitro clearance

7. Taking into account the analyte input analyte (C in ) (C out ) Limiting factors analyte supply = Q x (C in ) capacity of the system to clear: Clint ° Q ° Clearance: in vitro vs. in vitro

8. Clearance : in vitro vs in vivo In vitro In vivo Diffusion analyte Flow (Q) °

9. Q x C in Q x C out Q x (C in - C out ) Cl = dX /dt C in (Driving concentration) = Q x [C in - C out ] C in o o o o = Q x E o flow extraction coefficient (ratio) Clearance: general model

10. Cl organ = Q organ x E organ Flow Flow organ Cl is the blood (plasma) volume which is totally cleared of the drug for a time unit. Clearance is expressed in terms of flow which makes its interpretation difficult for a clinician organism Clearance: general model extration ratio (0 to 1) no unit

11. Cl organ = Q organ x E organ = Q x organism C in - C out C in Cl organ = = organis m Rate of elimination C in Rem.:C in for an organism is the aortic blood concentration C in for an organ is either the aortic blood (eg. kidney) or portal blood (e.g.. liver) concentration Mass per time Concentration o o Clearance: general model

12. Quantifies elimination Is usually constant ( a parameter) Parameter controlling exposure (AUC) Relevance of the clearance concept

13. For its usefulness –e.g.: dose computation For its mechanistic value –understanding of mechanism Relevance of the clearance concept

14. 1. To the whole body –plasma clearance (body, blood) 2. To a specific organ –liver / kidney / others 3. in vitro systems –hepatocytes (extrapolation from in vitro to in vivo) Application of the clearance concept

15. Classification of clearances (Cl) By organ liver : Clh kidney : Clr By mechanism metabolic clearance (Clh) excretion clearance (Clr) With respect to the matrix fluid blood plasma Application of the clearance concept