phrm 3052 week 2 - clearence 2
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7/30/2019 PHRM 3052 Week 2 - Clearence 2
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PHRM 3052
Biological Fate of Drugs B
Lecture 3
7/30/2019 PHRM 3052 Week 2 - Clearence 2
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Objectives
• To understand what CL is and to what it
refers
• To understand the practical value of CL
• To understand the relationship between
AUC and CL
• To understand…..
7/30/2019 PHRM 3052 Week 2 - Clearence 2
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• The most common definition of CL is:
“The volume of blood cleared of drug per unit time.” Avery’s Drug Treatment p.9
• In essence this is meaningless by virtue that it isimpossible to completely clear a portion of bloodcompletely of drug
• However, this description does show the unitsare volume per time (e.g. L/h)
2nd definition of CL – and least useful!
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• To make sense of the units it is importantto think about how clearance may beestimated experimentally …
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A possible experiment
Measure theconcentration
from theefferent artery
Measure theconcentrationfrom theafferent artery
LIVER
Ability of the liverto get rid of thedrug is given by
the extraction:
in
out in
Cp
CpCp E
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But extraction isn’t clearance…
• Extraction is the fraction of drug that is removed from asingle pass through the organ (e.g. liver)
• To compute clearance we need to consider how muchdrug gets to the organ…
• Since drug is carried in the blood then this can be doneby considering the perfusion of the organ (Q) hence
CL = Q (L/h) x E (no units)
i.e. clearance is the product of the perfusion and theintrinsic ability of the organ to eliminate the drug
Chapter 4, PK Made Easy
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Extraction ratio (E)
• The liver extraction EH is a function of the
unbound drug fraction, intrinsic clearance
and the liver perfusion:
• Since CL = Q.E then
int
int
..
CL f QCL f E ub H
ub H
int
int
.
.
CL f Q
CL f QCLub H
ub
H H
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Intrinsic Clearance (CLint)
• This is the theoretical maximum rate at which a
drug can be cleared
• It is proportional to the maximum rate at which
the drug can be metabolised (Vmax) andinversely proportional to the affinity of the drug
for the enzyme (KM)
CLint = Vmax / KM
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Simplifying CL
(Drugs are either high CL or low CL)
• For drugs of low CL, i.e. the intrinsic ability to clear the
drug f ub x CLint is << QH then the rate limiting step will be
the unbound intrinsic CL
CLH f ub.CLint
int
int
.
.
CL f Q
CL f QCL
ub H
ub
H H
QH + f ub.CLint QH
7/30/2019 PHRM 3052 Week 2 - Clearence 2
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Simplifying CL
(Drugs are either high CL or low CL)
• For drugs of high CL, i.e. the intrinsic ability to clear the
drug f ub x CLint is >> QH then the rate limiting step will be
liver perfusion (QH)
CLH QH
int
int
.
.
CL fubQ
CL fubQCL
H
H H
QH + f ub.CLint f ub.CLint
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A 3rd definition of CL
Clearance is the product of organ perfusion and
the intrinsic ability of the organ to eliminate the drug.
• This is the most meaningful physiologicalrelationship since:
– Any pathology that reduces organ perfusion (eg heartfailure) will reduce clearance.
– Any pathology that reduces organ function (eg acutetubular necrosis) will reduce clearance.
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Other nice things about CL
• Most organ systems in the body run in parallel –this means that the overall clearance is additive.Hence:
CL(total body) = CL(renal) + CL(liver) +CL(lung) + CL(bile) +…
• It is possible to obtain good estimates of CL basedon measures of organ function (e.g. creatinineclearance provides useful information about therenal clearance of many drugs)
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How do we determine clearance clinically?
Since MDrate = CL x Css,ave then:
CL = MDrate /Css,ave
MD is known – we need to know the average
Css,ave (too hard)
0
5
10
15
20
0 12 24 36 48 60
time (hours)
c o
n c e n t r a t i o n
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Getting around the average steadystate concentration problem
• The average steady state concentration (mg/L)
when multiplied by the dose interval () is the
same as the area under the concentration-time
curve (AUC) for the dose interval (0-). – What is the AUC?
– How is it calculated?
– Why is that?
– So what?
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What is AUC?
• AUC is the area under the concentration-timecurve.
• It represents the total systemic exposure of the
body to a dose of drug.• It may be estimated …
– Conduct an experiment where you give a
subject a dose of drug and then take about12 blood samples and measure theconcentration of drug in each sample…
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0
5
10
15
20
25
0 2 4 6
time (hours)
c o n c e n t r a t i o n
How is AUC0- estimated?
• First lets compute the AUC…
• Divide the curve intotrapezoids with area =base x average height
• Add up the area withineach trapezoid
• The sum of the areas =the AUC
trapezoids
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Why is Cpss(ave) x = AUC0-
SinceThe area in thetrapezoid = the area in
the rectangle withheight given as the aveheight of the trapezoid
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then
0 hr
0 hr
hr
hr
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huh?
since
and
then
)/(
)/()/(
, Lmg C
hour mg doseh LCL
ave ss
ave ssC AUC ,0
)/.(
)/()/(
0 Lhmg AUC
mg doseh LCL
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AUC CL
• Therefore if we can estimate AUC by doing anintensive PK study then we can get an estimateof CL
– From an estimate of CL we can determine thebest dosing regimen for an individual
– From estimates of AUC from lots of individualswe can get estimates of CL and thereforeestimate the variability in CL
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Summary of CL
• We can estimate clearance clinically andexperimentally
• It is the most important PK parameter
• Has useful relationships with physiological andpathophysiological processes
• Knowledge of the value of CL and the desired Cp
determines the dose that should be used!
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• A knowledge of CL does not allow one tocalculate the dose schedule – just the dose
rate.i.e. you can calculate that the desirable doserate might be 240 mg/24 hours fromknowledge of CL – but you cannot determine
from CL alone whether the dose should begiven as:
480 mg q48h
120 mg q12h
60 mg q6h10 mg/h
or some other dose interval …
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