Download Intrinsic Clearance

Intrinsic Clearance
Arthur G. Roberts
Hydrophobic vs. Hydrophilic
• more bound to plasma proteins
• more distributed throughout body
• more metabolized
Hypothetical Example
Kr
Km = rate constant for formation of metabolite Y
= rate constant for the elimination of drug X
= not the Michaelis-Menten constant
Kr = rate constant for the excretion of drug Y
slow
fast
Kr
* Slowest Step Determines the Rate
rel. fast
slow
Kr
* Slowest Step Determines the Rate
Concentration
dose (mg)
[Drug] =
Volume Distribution (L)
“Steady State” Concentration
drug infusion rate (mg/hr)
[Drug]steady state=
total body clearance (L/hr)
drug going in (mg/hr)
[Drug]steady state=
drug going out (L/hr)
Extraction Ratio (Efficiency)
• Extraction Ratio = ([Drug]in-[Drug]out)/[Drug]in
• Organ Clearance = Blood Flow (L/hr) (Q)*
Extraction Ratio (E)
[Drug]in
artery
Liver
[Drug]out
vein
Elimination
Effect on Clearance
Hepatic Clearance
• Major site of metabolism
• Pass through liver before systematic (First
Pass)
– receives most blood supply from GI.
BODY
LIVER
HEART
Portal
Vein
GUT
Artery
12
BODY
LIVER
HEART
Portal
Vein
GUT
Artery
13
BODY
LIVER
HEART
Portal
Vein
GUT
Artery
14
BODY
LIVER
HEART
Portal
Vein
GUT
Artery
15
BODY
LIVER
HEART
Portal
Vein
GUT
Artery
16
BODY
LIVER
HEART
Portal
Vein
GUT
Hepatic
Artery
17
Michaelis-Menten and Intrinsic
Clearance
Liver
[Drug]in
slow
fast
E+S ES  P
vein
artery
fast
S=Drug
P=Metabolite
[Drug]out
Elimination of P
Michaelis-Menten vs. Intrinsic
Clearance
[S]=[Drug]
Vmax[S]
v=
Km + [S]
v = velocity = ([S]*Volume Metabolized (L))/hour
Clint = v/[S] (Volume Metabolized (L))/hour
Vmax
v
Clint=
=
[S]
Km + [S]
v
Extraction Ratio and Intrinsic
Clearance
Clint (L/hr)
Extraction Ratio =
Blood Flow (L/hr) + Clint (L/hr)
Can the intrinsic clearance be higher than the blood flow?
If an enzyme that is involved in metabolizing a drug is induced, what is the
effect on Clint?
Intrinsic (Clint) and Hepatic Clearance
(Clh)
Clh = Hepatic Blood Flow (Qh) * Extraction Ratio (E)
Clint (L/hr)
Extraction Ratio (E) =
Blood Flow (L/hr) (Qh) + Clint (L/hr)
Qh * Clint (L/hr)
Clh =
Qh (L/hr) + Clint (L/hr)
Modeling Hepatic Clearance
Conc. along
Liver
Output Conc.
after going
through the
liver
Well Stirred Model
Assuming the Drug is 100% Unbound and Free to get Metabolized
Qh * Clint (L/hr)
Clh =
Qh (L/hr) + Clint (L/hr)
Assuming that there is a fraction of unbound drug (Funbound).
Qh * Funbound * Clint (L/hr)
Clh =
Qh (L/hr) + Funbound* Clint (L/hr)
Clint=Cli = intrinsic clearance
Clint (L/hr)
E=
Qh (L/hr) + Clint (L/hr)
End of Intrinsic Clearance