Week 6A physiological Flashcards
Clearance route
– kidneys (25% for 200 drugs)
• filtration, secretion
– liver
• metabolism: CYPs and UDPGs
• biliary secretion (<10%)albumin
major blood protein that binds drugs (~35 to 50 g/L)
Assumption of physiological clearance model
only unbound drug is available for clearance
• the physiological approach allows prediction of
the change in drug disposition due to
– alteration in organ blood flow
– enzymatic activity
– protein binding
physiological approach enables prediction of
overall drug disposition based on
– effects of diseases
– pharmacokinetic drug-drug interactions
organ clearance represents
the clearance of drug by a specific organ
hepatic clearance
volume of blood that is completely cleared from the drug per unit time by the liver
CL is additive
exception:
does not hold for drugs with significant pulmonary clearance, like volatiles (propofol)
intrinsic clearance (Clint)
• Liver intrinsic ability to metabolize (or secrete) drug
• Enzyme/transporter induction and inhibition can alter the liver intrinsic ability to eliminate drug
• ability of the liver to remove drug independent of blood
flow and protein binding
– a major part of this parameter is metabolism (inherent ability of hepatic enzymes to eliminate drug)
Hepatic blood flow (Qh)
Congestive heart failure and beta blockers can decrease cardiac output and affect liver blood flow
protein binding
fu – fraction unbound
drugs that are bound to proteins are not easily cleared by liver because only free drug crosses the cell membrane into tissue
hepatic drug clearance is a function of
intrinsic clearance, hepatic blood flow, and protein binding
Well-stirred model of organ clearance
hepatic/liver, kidney
• the rate of drug entering the liver is the product of
hepatic blood flow (Q) and the concentration of drug in
the arterial blood (Ca)
• the rate of drug leaving the liver is the product of
hepatic blood flow (Q) and the concentration of the drug
in the venous blood (Cv)
• Rate of drug elimination (Rin – Rout) = Q (Ca – Cv)
extraction ratio
measure of the organ efficiency in eliminating the drug during a single pass through the organ
• E is NOT the fraction of dose eliminated by metabolism
venous equilibrium model (Relationship Between Extraction Ratio and Hepatic CL)
– hepatic clearance can be determined by dividing
the hepatic elimination rate by the plasma
concentration
where QH is the hepatic blood flow (~ 1.3 L/min)
high (>0.7) Hepatic E of Drugs
lidocaine, morphine, nitroglycerin, propanolol, verapamil
this means when they get passed through the liver, they’re largely removed from the free drugs from blood circulation
intermediate (0.3 - 0.7)
nifedipine
low (<0.3)
diazepam, naproxen, phenytoin, theophylline, warfarin
•hepatic blood flow is ~ 20 ml/min/kg and may
be altered by disease (e.g. hepatic failure) or
drugs (e.g. beta-blockers)
blood enters liver through portal vein and hepatic artery and leaves through hepatic vein
– after oral dosing, drug is absorbed from GI tract into mesenteric vessels and proceeds to hepatic portal vein, liver and systemic circulation
For oral drugs which are completely absorbed
into portal circulation, the bioavailability depends
on the extraction ratio
F = 1 - E (first pass effect)
• flow from portal vein into liver is 1 L/min
• for high extraction ratio drugs the bioavailability is much less than for low extraction ratio drugs
• factors that alter E will affect F of orally administered drugs
– the hepatic clearance of drugs that have high
extraction ratios and high Clint values
(e.g., propranolol) are most affected by changes in blood
flow
the hepatic clearance of drugs that have low extraction
ratios and low Clint values
(e.g., theophylline) is most affected by changes in protein binding and enzyme activity
• an increase in blood flow reduces
hepatic extraction ratio (greatest reduction for drugs with low intrinsic clearance)
• hepatic clearance and rate of hepatic elimination may still increase due to the increase in blood flow (CLH = Q x E)
hepatic intrinsic clearance can change due
to
enzyme induction, inhibition, or due to diseases that affect liver function and decrease drug metabolism
- if metabolic enzyme goes up
for high intrinsic clearance drugs:
– CL is dependent on QH
– at high values of Clint, changes in Clint result in
very small changes in E (almost all the drug is
extracted anyway)
for low intrinsic clearance drugs:
– enzyme activity is rate limiting step (i.e. CL depends on liver enzymes)
– the CL is low and directly proportional to enzyme activity
low E drugs
CLint = 0.05, 0.1, 0.2, 0.4
long half life, higher F (minor effect). sig increase in E, CLh, and k
HEPATIC BLOOD FLOW
- increase in liver blood flow produces an insignificant change in CLh and F
maximum flow rate of liver
1.5 L/min
high E drugs
CLint= 10, 20, 30, 40
– does not significantly affect E, CLh, CLt and k following iv administration
– after oral administration, slight increase in E which decreases F significantly
– because the F of high E drugs is low, significant change in drug conc time profile
- Increases CLint
HEPATIC BLOOD FLOW
-the increase in liver blood flow produces a significant increase in CLh, F, k and CLt after IV administration
- after oral administration, k increases due to increase
in blood flow; however, increased blood flow reduces
E. F changes significantly
high E drugs PROTEIN BINDING
elimination depends on hepatic blood flow, changes in protein binding do not affect CLh (drug molecules can be stripped from their protein binding sites in liver)
high E drugs are relatively insensitive to PPB
• low E drugs with low PPB (<75%)
PPB - PLASMA PROTEIN BINDING
– elimination rate does not change significantly due to
change in protein binding (small change in free drug
concentration)
low E with high PPB (> 75%)
elimination rate is very sensitive to changes in protein
binding (small change in PPB results in significant
change in free drug concentrations and increase in
rate of elimination)
