E1 L7: Bioavailability and Clearance 2 Flashcards
What determines EH?
Intrinsic clearance = represents how good a compound is a substrate for different drug metabolizing enzymes
Large = good candidate = rapid elimination when seeing enzyme
EH
Hepatic Extraction Ratio
Max organ clearance values are equivalent to the
Blood flow to the organ
Fraction of hepatic plasma flow from which drug is completely cleared
E
CL =
QH * EH
A fraction of drug eliminated by liver during single pass
Efficiency of liver to eliminate a drug
Values range from 0 (no metabolism) to 1 (complete metabolism)
Hepatic extraction ratio (EH)
Volume of plasma from which a drug is completely eliminated (removed) by liver per unit time
Unit: volume/time e.g L/h, ml/min
Drug-dependent parameter
Values range from 0 to hepatic plasma flow (i.e. QH)
Hepatic Clearance (=QH * EH)
High and Low EH drug values
High: >0.7
Low <0.3
Low EH drugs
Theophylline
Warfarin
High EH drug
Verapamil
Low EH drug properties
High protein binding and/or low enzyme activity against a drug limit hepatic elimination
High EH drug properties
These drugs are good substrates of drug-metabolizing enzymes, and protein binding does not limit metabolism
Reflects the natural ability of the liver to metabolize a drug, independent of binding restrictions
CLint (intrinsic clearance)
CLint properties
Property of a drug, just as VD, Kel and CL are
Unit: Volume/time
Values are greater than 0, but there is no upper limit
is Calculated from in vitro experiments (using liver tissues)
Are the ones that are rapidly metabolized by the liver when the drugs are in unbound (free) form
Drugs of high CLint
Are the ones that it takes longer to be metabolized even if the drugs are in unbound form
Drugs of small CLint
Enzyme inhibitors (increase/decrease) CLint
Decrease
Enzyme inducers (increase/decrease) CLint
Increase
Low EH drugs: Increasing free fraction of drug would have - effects on its EH
Significant
High EH drugs: Increasing free fraction of drug would have - effects on its Eh
Insignificant
Unbound fraction
fu
Well-stirred model equation
CLH = Fu * CLint
Hepatic plasma flow
QH
Well-stirred model: B-force
The more drug you have as free form, the better B force will be
B force is represented by the free fraction of the drug, and the intrinsic clearance of the drug
Low EH drugs equation
CLH = fu * CLint
High EH drugs equation
CLH = QH
Factors affecting CLH
Hepatic Plasma Flow (QH):
Decreased by disease states like heart failure, liver disease, beta blockers
Increased by food
Hepatic enzyme activity (CLint)
Decreased by liver disease, dietary deficiencies, enzyme inhibiting drugs such as cimetidine
Increased by enzyme inducing drugs such as rifampin, and environmental pollutants including cigarettes
Binding to plasma proteins (fu)
Plasma proteins (albumin) are synthesized in the liver. Chronic liver diseases such as cirrhosis decrease circulating plasma protein concentrations
PK parameter reflecting the rate of drug elimination from the body
CL
PK parameter reflecting the rate of drug elimination from the liver
CLH
Pk Parameter reflecting the rate of drug metabolism by hepatic drug-metabolizing enzymes
CLint
Q: Drug A is eliminated 100% by hepatic metabolism. Drug A’s CL is 100ml/min
T/F:
1: Drug A is a high EH drug
2. Drug A’s fe = 0
3. Rifampin will likely increase CLint of drug A
- False (CLH/QH = 100/700 = 0.14)
- True
- True
Q: T/F: Rifampin will likely increase CLH of of Low EH drugs
True (CLint = CLH)
Q: T/F: Rifampin will likely increase CL of low EH drugs
True (CL = CLH)
Q: T/F: B-blockers will likely decrease CL of Low EH drugs
False - Decreased QH
Q: Drug B is eliminated 100% by hepatic metabolism. Drug B’s CL is 600 mL/min
T/F:
1. Drug B is a high EH drug
2. Drug B’s fe = 0
3: Rifampin will likely increase CLint of Drug B
- True (600/700=0.86)
- True (fe is 0, drug is eliminated by hepatic 100% - no parent drug in urine)
- True (CL reflects how fast drug metabolizes drug B, it will go up)
Q: T/F: Rifampin will likely increase CLH of High EH drug
False: CLH = QH
Q: T/F: Rifampin will likely increase CL of High EH drug
False (CL = CLH)
Q: T/F: B-blockers will likely decrease CL of Drug B
True (Decreased QH = true)
