phrm 3052 week 2 - clearence 2

7/30/2019 PHRM 3052 Week 2 - Clearence 2

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PHRM 3052

Biological Fate of Drugs B

Lecture 3



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…..



• 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!



• To make sense of the units it is importantto think about how clearance may beestimated experimentally …



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



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



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



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



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



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



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.



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)



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



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?



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…



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



Why is Cpss(ave) x = AUC0-

SinceThe area in thetrapezoid = the area in

the rectangle withheight given as the aveheight of the trapezoid



then

0 hr

0 hr

hr

hr



huh?

since

and

then

)/(

)/()/(

, Lmg C

hour mg doseh LCL

ave ss

ave ssC AUC ,0

)/.(

)/()/(

0 Lhmg AUC

mg doseh LCL



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



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!



• 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 …

phrm 3052 week 2 - clearence 2

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