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Case Study โ 3 PHA 5127 โ Fall 2006
1: Predict the changes in Cl h
given the following scenarios:
Parameter
Direction of change
effect on Cl h
for a
low Extraction
drug
effect on Cl h
for a
high Extraction
drug fraction of
unbound drug
Increases increases
no significant
changes intrinsic clearance
Decreases decreases
no significant changes
hepatic blood flow
Increases
no significant changes
increases
Low Extraction Drug
int
int
int
CL f CL
Q f CL
Q f CL CL
hep u
hep u
hep u hep
High Extraction Drug
hep hep
hep u
hep u hep
CL Q
Q f CL
Q f CL CL
int
int
2: True or False Questions
T F Total clearance is dependent on the half-life of the drug.
T F Volume of distribution and clearance are two major pharmacokinetic
parameters, and they are dependent on each other based on equation:
CL = Vd โ
k e
T F Clearance defines the amount of drug eliminated from body per unit time.
T F According to the equation:
Vd ke
Dose
CL
Dose
AUC
โ = = , the change of
volume of distribution does affect AUC โ.
T F Intrinsic clearance is not dependent on blood flow, and it represents the
activities of enzyme system when we talk about liver metabolism.
T F Liver blood flow affects high extraction drug much more than low
extraction drug when drug major elimination pathway is hepatic elimination.
3: Gamma-hydroxybutyric Acid (GHB) is an abused drug and also an endogenous
compound. Recently, a study in rats was carried out to understand pharmacokinetics of
GHB. A couple of rats were given a dose at 100mg intravenously in this study. Blood
samples were taken at several time points. A graduate student in this lab plotted
concentration-time data. He found that drug concentration-time profile can be best
described by a one-compartmental linear model. He also determined that total clearance
is 150 mL/hr, and t 1 / 2 is 0.5 hr.
A: Calculate Volume of Distribution of GHB, GHB concentration at time zero,
and AUC โ.
Dose = 100 mg
CL = 150 mL/hr
t 1 / 2 = 0.5 hr
ln 2 0. 6931
1 / 2
โ
= = = hr
t
k e
1
1
ml
hr
ml hr
k
CL
V
e
d =
โ
0 mg ml
ml
mg
V
Dose
C
d
1 mg ml hr
ml hr
mg
CL
Dose
AUC = โ
โ =^ = โ
B: If liver metabolism is the major elimination pathway for GHB in rat, blood flow rate
in rat is 1.5 L/hr, what is the extraction ratio for GHB in liver?
Cl = Q โ
E
Q = 1. 5 ( L / hr )= 1500 ( ml / hr )
CL = 150 mL/hr
Cl = Q โ
E
ร 150 ml^ / hr =^1500 ml / hr โ
E
ร E = 0. 1
C: According to the Question B, is GHB a high or low extraction drug? If the free
fraction of GHB in plasma is 0.3, what is the intrinsic clearance?
