Clearance Determinations Arthur G. Roberts
Routes of Elimination
Zero versus First-Order Elimination
Zero Order
First Order
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]
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
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
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
Example Rate Drug in, Rate Drug out, Extraction rate, extraction ratio, Clearance, Elimination Rate 1 L/(kg*hr) Kidneys Continuous IV infusion
Clearances
Clearance is additive sometimes Cl h
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
Total Body Clearance [Drug] plasma
Renal Clearance Loop of Henle Proxima l Tubule Distal Tubule Collecting Duct
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
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 = ?
Tubular Secretion
Tubular Reabsorption Lipophilicity pKa (acid and base forms)
Renal Clearance Renal Clearance (Cl r ) = Cl GF + Clearance from Tubular Secretion (Cl TS ) – Tubular Reabsorption (TR) Cl r = fu * GFR + Cl ts - TR
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)?
Renal Clearance [drug] plasma
Cl r Example PeriodVolume[Drug] urine Period[Drug] plasma Average Excretion Rate (mg/hour) = (Volume * [Drug] urine )/time 3 mg/hour = ( 0.2 *15)/1 mg/L hours L
Cl r Example PeriodAvg. Excretion Rate Period[Drug] plasma mg/L hours mg/hour slope = ( )/( ) slope = 2.72/0.219=12.4 L/hour=Cl r
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/L mg/L Plasma Creatine Concentration 10 mg/L6-12 mg/L 55 year old 65 kg female What is the average Cl r ?
Hepatic Clearance Mechanisms Biotransformation Excretion
Restrictive and Non-restrictive Clearance Non-restrictive E h > 0.7 Restrictive E h < 0.3
Non-Restrictive Hepatic Clearance: High E h
Restrictive Hepatic Clearance: Low E h
Blood and Plasma Hepatic Clearance plasma = protein and water
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?
End of Clearance Determinations