1 hepatic clearance q x c a q x c v q(c a - c v ) rate of extraction 1. mass balance
TRANSCRIPT
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HEPATIC CLEARANCE
Q x CA Q x CV
Q(CA - CV)
Rate of Extraction
1. Mass Balance
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HEPATIC CLEARANCE
Extraction Ratio
2. Mass Balance Normalized to Rate of Entry
1 1 - E
E
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HEPATIC CLEARANCE
Clearance
3. Mass Balance Normalized to CA
Q Q(1 – E)
Q x E
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Recall that CL = QE; hence
CLH = QHE
CLH = hepatic clearance QH = hepatic blood flow E = hepatic extraction ratio QH - from 1.0 to 1.5 L/min E – ranges from 0 to 1
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Recall that CL = QE; hence
CLH = QHE
Thus, if the non-renal clearance of a drug exceeds QH, some form of non-renal and non-hepatic elimination must take place.
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Example: (labetalol)
CLT = 2.344 L/minCLR = 0.08 L/min Vss = 685 L t1/2 = 6 hr
Can the nonrenal clearance be attributed solely to hepatic elimination?
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CLH = QHE
Suggests that
CLH ~ QH
Actually
QH = E
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VENOUS EQUILIBRIUM MODEL
QCin QCout
Elimination
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SINUSOIDAL MODEL
QCin QCout
Elimination
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int
int
CLQ
CLE
H
Intrinsic hepatic clearance: The ability of the liver to remove xenobiotic from the blood in the absence of other confounding factors (e.q., QH).
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int
int
CLQ
CLE
H
Since
CLH = QHE
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int
int
CLQ
CLQCL
H
HH
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Quantitative Assessment of Hepatic Clearance
Assuming the Venous Equilibrium Model
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Assuming Q constant at 1 L/min
0
0.5
1
CLint
E
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CLint of 0.1, 1.0, and 10.0 L/min
0
0.2
0.4
0.6
0.8
1
0 1 2 3
Q
E
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Limits:
HH Q
CLECLQ int
int then ,When
HH Q
CL
CLQ
CLE int
int
int Because
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Limits:
1 then ,When int ECLQH
1 Becauseint
int
CLQ
CLE
H
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CLint of 10, 1.0, and 0.1 L/min
0
0.5
1
1.5
2
0 1 2 3
Liver Blood Flow, L/min
He
pa
tic
Cle
ara
nce
, L
/min
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Limits:
int
int
then
,When
CLCL
CLQ
H
H
intint
int CLCLQ
CLQCL
H
HH
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Limits:
HH
H
QCL
CLQ
then
,When int
HH
HH Q
CLQ
CLQCL
int
int
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HH
HH Q
CLQ
CLQCL
int
int
Compounds with a high CLint, are said to exhibit perfusion rate-limited elimination.
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From: Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications, 3rd edition, 1995, p. 162
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HEPATIC EXTRACTION RATIO OF REPRESENTATIVE DRUGS
Low (<0.3)AntipyrineDiazepamPhenylbutazoneTheophyllineTolbutamideWarfarin
High (>0.7)LidocaineMeperidinePropoxyphenePropranololVerapamil
Intermediate: Quinidine
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Consider the case of administering a constant infusion of a drug with the following conditions:
CLint = 7.0 L/min, QH = 1.0 L/min Ko = 1.0 mg/min
Assuming drug is eliminated completely via hepatic metabolism, what would the steady-state concentration be?
int
int
CLQ
CLQCL
H
HH
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L/min 0.875L/min 7.0 L/min 1.0
L/min 7.0 L/min 1.0
HCL
mg/L 14.1 L/min 0.875
mg/min 1.0
0
H
ss CL
KC
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What if the pt developed CHF resulting in a 25% reduction in QH?
L/min 0.677 L/min 7.0 L/min 0.75
L/min 7.0 L/min 0.75
int*
int*
*
CLQ
CLQCL
H
HH
mg/L 48.1L/min 0.677
mg/min 1.0*0* H
ss CL
KC
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In contrast, suppose we administer a low CLint?
CLint = 0.01 L/min, QH = 1.0 L/min K0 = 0.1 mg/min
L/min 0099.0L/min 0.01L/min 1.0
L/min 0.01L/min 1.0
HCL
mg/L 10L/min 0.0099
mg/min 0.1ssC
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What if QH were reduced by 25%
L/min 0099.0L/min 0.01 L/min 0.75
L/min 0.01 L/min 0.75*
HCL
mg/L 10 L/min 0.0099
mg/min 0.1* ssC
mg/L 10ssC
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FIRST-PASS EFFECT
HEART
GUT
LIVER BODY
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HEART
GUT
LIVER BODY
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HEART
GUT
LIVER BODY
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HEART
GUT
LIVER BODY
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HEART
GUT
LIVER BODY
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HEART
GUT
LIVER BODY
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If a drug is completely absorbed after oral administration, the fraction of the oral dose that reaches the systemic circulation (F) is given as
F = 1 - E
Remembering that
int
int
CLQ
CLE
H
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int
int1CLQ
CLF
H
intCLQ
QF
H
H
QH >> CLint, F1QH << CLint, F0
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Assuming CLint constant
0
0.5
1
Hepatic Blood flow
F
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Determination of CLint after oral dosing:
Assumes:•Drug is completely absorbed•No extrahepatic metabolism•System is stationary
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Determination of CLint after oral dosing:
o
oH AUC
DFCL
int
int
CLQ
CLQCL
H
HH
intCLQ
QF
H
H
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Determination of CLint after oral dosing:
o
o
H
H
H
H
AUC
D
CLQ
Q
CLQ
CLQ
intint
int
o
o
AUC
DCL int
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Estimated in this fashion the CLint is often referred to as the oral clearance (CLo)
For a high CLint drug:
Hiv
iv CLAUC
D
intCLAUCo
Do
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Estimated in this fashion the CLint is often referred to as the oral clearance (CLo)
For a low CLint drug:
intCLCLAUC
D
AUC
DH
o
o
iv
iv
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Consider a high clearance drug (e.g., propranolol) after oral and IV dosing:
CLint = 10 L/min, QH = 1.5 L/min
L/min 1.304 L/min 10 L/min 1.5
L/min 10 L/min 1.5int
int
H
H
H
HH
CL
CL
CLQ
CLQCL
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L/min 1.304 HCL
What would happen to CLH is QH were reduced to 1.0 L/min?
L/min 909.0L/min 10 L/min 1.0
L/min 10 L/min 1.0
HCL
What if drug were administered orally under these conditions?
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0.869 L/min 10 L/min 5.1
L/min 10int
int
E
E
CLQ
CLE
H
13.0869.011 EF
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13.0869.011 EFHow would a decrease in QH affect this?
091.0909.01
909.0
L/min 10 L/min 0.1
L/min 10
*
*
*
F
E
E
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But what happens to AUC?
H
oo
o
oH CL
FDA
AUC
FDCL UCor
For control conditions:
min/Lmg 10 L/min 1.304
(0.13) mg 100oAUC
When QH is decreased:
min/Lmg 10 L/min 0.091
(0.091) mg 100oAUC
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IMPACT OF PROTEIN BINDING
CLint = fubCLuint
int
int
uubH
uub
CLfQ
CLfE
int
int
uubH
uubHH CLfQ
CLfQCL
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int
int
uubH
uubHH CLfQ
CLfQCL
intint then , uubHuubH CLfCLCLfQWhen
HHuubH QCLCLfQWhen then , int
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Effect of protein binding on warfarin clearance in the rat . Data from Yacobi A, Levy G. J Pharm Sci 64:1660, 1975.
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Effect of protein binding on warfarin clearance in humans. Data from Routledge et al. Br J Clin Pharmacol 8:243, 1979.
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CLuint = 0.25 L/min QH = 1.5 L/minfub = 0.1 K0 = 0.25 mg/min
L/min 0.0246
L/min) 0.250.1(L/min 1.5
L/min 0.250.1L/min 1.5int
int
H
H
uubH
uubHH
CL
CL
CLfQ
CLfQCL
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CLuint = 0.25 L/min QH = 1.5 L/minfub = 0.1 K0 = 0.25 mg/min
L/min 0.0246 HCL
mg/L 10.2 L/min 0.0246
mg/min 25.0
0
ss
ss
Hss
C
C
CL
KC
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What if fub = 0.2?
L/min 0.0484
L/min) 0.250.2(L/min 1.5
L/min 0.250.2L/min 1.5
*
*
int*
int*
*
H
H
uubH
uubHH
CL
CL
CLfQ
CLfQCL
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What if fub = 0.2?
L/min 0.0484 * HCL
mg/L 5.16
L/min 0.0484
mg/min 25.0
*
*
0*
ss
ss
Hss
C
C
CL
KC
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mg/L 10.2 ssC mg/L 5.16 * ssC
What happens to free concentration?
mg/L 1.02 0.1 mg/L 10.2 ubssss fCC
Control
fub
mg/L 1.03 0.2 mg/L 16.5*** ubssss fCC
Change
fub
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What about oral administration?
98.0
L/min) 0.25(0.1 L/min 1.5
L/min 0.250.11
1int
int
F
F
CLfQ
CLfF
uubH
uub
97.0
L/min) 0.25(0.2 L/min 1.5
L/min 0.250.21
*
*
F
F
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58
Consider a high clearance drug iv:
CLuint = 30 L/min QH = 1.5 L/minfub = 0.25 K0 = 2 mg/min
L/min 1.25
L/min) 300.25(L/min 1.5
L/min 300.25L/min 1.5int
int
H
H
uubH
uubHH
CL
CL
CLfQ
CLfQCL
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59
Consider a high clearance drug iv:
CLuint = 30 L/min QH = 1.5 L/minfub = 0.25 K0 = 2 mg/min
L/min 1.25HCL
mg/L 1.6L/min 1.25
mg/min 20 H
ss CL
KC
mg/L 0.40.25mg/L 1.6 ubssss fCCfub
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60
What if fub = 0.5?
L/min 1.36
L/min) 300.5(L/min 1.5
L/min 300.5L/min 1.5
*
*
int*
int*
*
H
H
uubH
uubHH
CL
CL
CLfQ
CLfQCL
![Page 61: 1 HEPATIC CLEARANCE Q x C A Q x C V Q(C A - C V ) Rate of Extraction 1. Mass Balance](https://reader035.vdocuments.net/reader035/viewer/2022062223/55162ffb550346a2308b5f9e/html5/thumbnails/61.jpg)
61
What if fub = 0.5?
L/min 1.36* HCL
mg/L 1.47L/min 1.36
mg/min 2*0* H
ss CL
KC
mg/L 0.730.5mg/L 1.47*** ubssss fCCfub
mg/L 0.4fubssC
mg/L 1.6ssC
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62
What about oral administration?
83.0L/min) 300.25(L/min 1.5
L/min 300.25int
int
E
CLfQ
CLfE
uubH
uub
min/Lmg 16.67
min/Lmg 66.67 L/min 1.25
0.83)-(1 mg 500
)1(
fubo
o
H
oo
AUC
AUC
CL
EDAUC
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63
What if fub = 0.5?
91.0.0L/min) 300.5(L/min 1.5
L/min 300.5*
int*
int*
*
E
CLfQ
CLfE
uubH
uub
min/Lmg 15.54
min/Lmg 30.9 L/min 1.36
0.91)-(1 mg 500
)1(
*
*
*
**
fubo
o
H
oo
AUC
AUC
CL
EDAUC
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64
What if fub = 0.5?
min/Lmg 15.54
min/Lmg 30.9 *
*
fubo
o
AUC
AUC
min/Lmg 16.67
min/Lmg 66.67
fubo
o
AUC
AUC
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65
Effect of displacement (D) of plasma protein binding on total and unbound concentrations of drug
From: Rowland M, Tozer TN. Clinical Pharmacokinetics – Concepts and Applications, 3rd edition
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66From: Rowland M, Tozer TN. Clinical Pharmacokinetics – Concepts and Applications, 3rd edition
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67
Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
1.0
0.1
Blo
od C
once
ntra
tion
E 0.1CLint 0.167 L/minCLH 0.150 L/min
Time
0.180.334 L/min0.273 L/min
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68
Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
1.0
0.1
Blo
od C
once
ntra
tion
Time
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69
Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
1.0
0.1
Blo
od C
once
ntra
tion
E 0.90CLint 13.7 L/minCLH 1.35 L/min
Time
0.9527.0 L/min1.42 L/min
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70
Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
0.1
0.01
Blo
od C
once
ntra
tion
Time
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71
Effect of rifampin on the kinetics of warfarin after a single dose before (open circles) and after (closed circles) treatment with rifampin 600 mg/day. From: O’Reilly RA. Interaction of sodium warfarin and rifampin. Ann Intern Med 81:337-40, 1974.
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72
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73
Effect of pentobarbital on alprenolol disposition. Alprenolol was administered before (O, closed, iv, open oral) and after 10 d of pentobarbital (). Reproduced from Alvan G, et al. Clin Pharmacol Ther 22:316-321, 1977.
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74
Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
1.0
0.1
Blo
od C
once
ntra
tion
E 0.1QH 1.50 L/minCLH 0.150 L/min
Time
0.180.75 L/min0.135 L/min
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75
Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
1.0
0.1
Blo
od C
once
ntra
tion
Time
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76
Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
1.0
0.1
Blo
od C
once
ntra
tion
E 0.90QH 1.50 L/minCLH 1.35 L/min
Time
0.950.75 L/min0.71 L/min
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77
Effect of changes in the determinants of hepatic clearance on the concentration versus time curves
0.1
0.01
Blo
od C
once
ntra
tion
Time
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78
Propoxyphene’s CNS depression is enhanced when co-administered with ethanol. To assess the contribution of a pharmacokinetic interaction to this enhancement, propoxyphene was administered iv and po, with and without ethanol. The curves below illustrate the results. What is the mechanism of interaction?
TIME
Log
[Pro
po
xyp
hen
e]
TIME
Log
[Pro
po
xyp
hen
e]
Propoxyphene alone Propoxyphene + ETOH
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79
Complete the following graphs for a drug with a CLH = 20 mL/min/kg and one with a CLH = 1 mL/min/kg
fup
CLH
fup
AUCo
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80
Complete the following graphs for a drug with a CLH = 20 mL/min/kg and one with a CLH = 1 mL/min/kg
fup
CLuint
QH
CLH
![Page 81: 1 HEPATIC CLEARANCE Q x C A Q x C V Q(C A - C V ) Rate of Extraction 1. Mass Balance](https://reader035.vdocuments.net/reader035/viewer/2022062223/55162ffb550346a2308b5f9e/html5/thumbnails/81.jpg)
81
Complete the following graphs for a drug with a CLH = 20 mL/min/kg and one with a CLH = 1 mL/min/kg
fup
CLuint
![Page 82: 1 HEPATIC CLEARANCE Q x C A Q x C V Q(C A - C V ) Rate of Extraction 1. Mass Balance](https://reader035.vdocuments.net/reader035/viewer/2022062223/55162ffb550346a2308b5f9e/html5/thumbnails/82.jpg)
82
Complete the following graphs for a drug with a CLH = 20 mL/min/kg and one with a CLH = 1 mL/min/kg
QH
CLH
![Page 83: 1 HEPATIC CLEARANCE Q x C A Q x C V Q(C A - C V ) Rate of Extraction 1. Mass Balance](https://reader035.vdocuments.net/reader035/viewer/2022062223/55162ffb550346a2308b5f9e/html5/thumbnails/83.jpg)
83
E QH fub fut CLT Vss t1/2 AUCo
High High High
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84
E QH fub fut CLT Vss t1/2 AUCo
Low
Low Low