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Understanding Clearance: From In Vitro to In Vivo Conceptual Framework

This document updates the concept of clearance in pharmacology, detailing its definition, calculations, and relevance in both in vitro and in vivo contexts. Clearance is defined as the volume of solution completely cleared of an analyte per unit time, helping quantify drug elimination and informing clinicians about drug exposure. The distinction between in vitro and in vivo clearance is explored, addressing factors like analyte supply and system capacity. Various applications are outlined, including total body plasma clearance and organ-specific clearance for better understanding of pharmacokinetics and dosage calculations.

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Understanding Clearance: From In Vitro to In Vivo Conceptual Framework

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

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

  3. Clearance : from in vitro to in vivo

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

  5. Clearance: in vitro vs. in vitro Taking into account the analyte input analyte (Cin) ° (Cout) Q • Limiting factors • analyte supply = Q x (Cin) • capacity of the system to clear: Clint °

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

  7. Clearance: general model o Q x Cin o Q x Cout o Q x (Cin - Cout) dX /dt [Cin - Cout] o o Cl = = Q x = Q x E Cin Cin (Driving concentration) extraction coefficient (ratio) flow

  8. Clearance: general model Clorgan = Qorgan x Eorgan Flow Floworgan organism organism organism extration ratio (0 to 1) no unit organism 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

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

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

  11. Application of the clearance concept 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)

  12. Application of the clearance concept • 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

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