clearance determinations arthur g. roberts. routes of elimination
TRANSCRIPT
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Clearance Determinations
Arthur G. Roberts
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Routes of Elimination
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Zero versus First-Order Elimination
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Zero Order
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First Order
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1st Order Elimination
rate of renal excretion = Krenal * [Drug]rate of metabolism = Kmetabolism * [Drug]rate of biliary excretion = Kbiliary * [Drug]rate of other = Kother * [Drug]
Overall elimination = sum of all the ratesOverall elimination = (Krenal+Kmetabolism+Kbiliary+Kother)*[Drug]
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Clearance, Elimination and Excretion
• Clearance (Renal) (V/time, L/hr)• Elimination (mass) (a.k.a. Extraction)• Mechanisms for either– biotransformation (e.g. Clint)– excretion
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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
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Clearance Terms
[Drug]in (mg/L) [Drug]out (mg/L)
Q (L/h) Q (L/h)
Rate of Drug in = [Drug]in * QRate of Drug out = [Drug]out * QExtraction Rate = ([Drug]in-[Drug]out ) * QExtraction Ratio ([Drug]in-[Drug]out)/[Drug]in)Clearance = E * Q
ArteryVein
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Example
Rate Drug in, Rate Drug out, Extraction rate, extraction ratio, Clearance, Elimination Rate
1 L/(kg*hr) 1 L/(kg*hr)
Kidneys
Continuous IV infusion
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Clearances
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Clearance is additive
sometimes Clh
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Elimination Rate Constant and Half Life Versus Clearance
• elimination rate = - K * Drug doseplasma = -Cl * [Drug]plasma
• K = Clearance (Cl)/Volume Distribution (Vd)• T1/2 = (ln 2)/K = (ln 2 * Vd)/Cl
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Total Body Clearance[D
rug]
plas
ma
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Renal Clearance
Loop of Henle
Proximal Tubule
Distal Tubule
Collecting Duct
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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
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Renal Clearance
• Neutral and small drug (< 8 nm)– not bound to plasma proteins• Glomerular Filtration Rate (GFR) = Clearance (ClGF)
– bound to plasma proteins• fraction unbound (fu) * GFR = ClGF
Example:
GFR = 9 L/hourfu = 30%CLGF = ?
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Tubular Secretion
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Tubular Reabsorption
• Lipophilicity• pKa (acid and base forms)
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Renal Clearance
• Renal Clearance (Clr) = ClGF + Clearance from Tubular Secretion (ClTS) – Tubular Reabsorption (TR)
• Clr = fu * GFR + Clts - TR
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Renal Clearance Example
Clr = 1.8 L/hr
GFR = 7.2 L/hr
fraction bound = 80%
What are the relative values for active tubular secretion (ClTS) and tubular reabsorption (TR)?
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Renal Clearance
[drug]plasma
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Clr Example
Period Volume [Drug]urine Period [Drug]plasma
0-1 0.2 15 0.5 0.240
1-3 0.180 19.4 2 0.142
3-5 0.140 12.8 4 0.071
5-10 0.4 3.5 7.5 0.021
Average Excretion Rate (mg/hour) = (Volume * [Drug]urine)/time3 mg/hour = ( 0.2 *15)/1
mg/L mg/Lhours hoursL
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Clr Example
Period Avg. Excretion Rate
Period [Drug]plasma
0-1 3 0.5 0.240
1-3 1.746 2 0.142
3-5 0.896 4 0.071
5-10 0.280 7.5 0.021
mg/Lhours hoursmg/hour
slope = (3-0.280)/(0.240-0.21)slope = 2.72/0.219=12.4 L/hour=Clr
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Single-Point Determination of Renal Clearance Under Steady-State Conditions
Measurement Amount Normal
Collection Period 24 hours
Volume Urine Collected
1.05 L
Urinary Creatine Concentration
1140 mg/L 400-3000 mg/L
Plasma Creatine Concentration
10 mg/L 6-12 mg/L
55 year old 65 kg female
What is the average Clr?
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Hepatic Clearance Mechanisms
• Biotransformation• Excretion
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Restrictive and Non-restrictive Clearance
• Non-restrictive Eh > 0.7
• Restrictive Eh < 0.3
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Non-Restrictive Hepatic Clearance: High Eh
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Restrictive Hepatic Clearance: Low Eh
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Blood and Plasma Hepatic Clearance
plasma = protein and water
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Example
• Clplasma hepatic = 54 L /hr
• Qhb = 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?
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End of Clearance Determinations