Bioavailability II

Which of the following is false in regards to Extraction ratio (E)?

a. Value ranges from 0 to infinity

b. A fraction of drug eliminated by a drug-eliminating organ during single pass metaboism

c. Efficiency of a drug-eliminating organ to eliminate a drug

d. Drug-dependent (property of drug)

a. Value ranges from 0 to infinity

Values range from 0-1

Which of the following is true about Extraction ratio (E)? (Select all that apply)

a. High E_H drugs have E_H > 0.7

b. High E_H drugs have E_H < 0.7

c. Low E_H < drugs have E_H < 0.3

d. Low E_H < drugs have E_H > 0.3

a. High E_H drugs have E_H > 0.7

c. Low E_H < drugs have E_H < 0.3

Which of the following are Low E_H drugs? (Select all that apply)

a. Verapamil

b. Rifampin

c. Cimetidine

d. Warfarin

e. Theophylline

f. Propranolol

d. Warfarin

• Has HIGH plasma protein binding 

e. Theophylline

• not a good substrate for drug-metabolizing enzymes

Which of the following are High E_H drugs? (Select all that apply)

a. Verapamil

b. Rifampin

c. Cimetidine

d. Warfarin

e. Theophylline

f. Propranolol

a. Verapamil

• Good substrate of drug-metabolizing enzymes (takes precedence)

• Has high plasma protein binding

What determines if a drug is Low_H?

a. If a drug is a good substrate of drug-metabolizing enzymes

b. If the drug is high protein-binding.

c. If the drug is present in small amounts.

d. If a drug has low enzyme activity (not a good substrate for drug metabolizing enzymes)

b. If the drug is high protein-binding.

d. If a drug has low enzyme activity (not a good substrate for drug metabolizing enzymes)

What determines if a drug is High E_H?

b. If the drug is high protein-binding.

c. If the drug is present in small amounts.

d. If a drug has low enzyme activity (not a good substrate for drug metabolizing enzymes)

a. If a drug is a good substrate of drug-metabolizing enzymes

• Is not limited by protein binding unlike low E_H drugs

Which is true about CL_int (intrinsic clearance)?

a. It reflects the natural ability of the liver to metabolize a drug in its free form (unbound form)

b. Drug-dependent (property of drug)

c. Values are greater than 0, goes to infinity

d. Drugs with large CL_int are rapidly metabolized by the liver while Drugs with small CL_int take longer to metabolize

e. All of the above are true

e. All of the above are true

True or false: CL_int can be measured directly from plasma concentrations.

False. CL_int is typically determined from in vitro systems (using liver tissues).

C_p gives CL (systemic) and CL_H (hepatic

Which of the following are enzyme inducers? (Select all that apply)

a. Erythromycin

b. Cimetidine

c. Phenobarbital

d. Rifampin

c. Phenobarbital

d. Rifampin

Which of the following are enzyme inhibitors? (Select all that apply)

a. Erythromycin

b. Cimetidine

c. Phenobarbital

d. Rifampin

a. Erythromycin

b. Cimetidine

Which of the following is false?

a. CL_int of a drug reflects how good a substrate a drug is to drug-metabolizing enzymes

b. CL_int reflects the ability of the liver to metabolize a drug also dependent of binding restrictions

c. Enzyme inhibitors inhibit activities of drug-metabolizing enzymes (i.e. Cimetidine)

d. Enzyme inducers induce expression of drug-metabolizing enzymes. (i.e. Rifampin)

b. CL_int reflects the ability of the liver to metabolize a drug also dependent of binding restrictions

If verapamil has high protein binding and high intrinsic clearance, what will happen to its hepatic extraction ratio (EH) if its free fraction (fu) increases?

a. significant effects on E_H

b. insignificant effects on E_H

b. insignificant effects on E_H

Verapamil is a high E_H drug, and in high E_H drugs, metabolism is not limited by protein binding. What matters is if a drug is a good substrate of drug-metabolizing enzymes.

• Verapamil is a good substrate

Which of the following has low enzyme activity against a drug limit hepatic elimination?

a. Warfarin

b. Verapamil

a. Warfarin

• Low E_H drug

Define the variables included in the Well-Stirred Model (E_H)

B (Force B) = extent of hepatic drug metabolism

• how well metabolism is show

• more free drug, more metabolism

A (Force A) = carries drug away from organ/metabolism site

f_u = unbound fraction

Q_H = hepatic plasma flow

CL_int = intrinsic clearance

Given this image and equation, what can you say about Low E_H drugs?

(Select all that apply)

a. Force A > > > Force B

b. has low enzyme activity; blood flow dominates (Q_H)

c. CL_H = f_u * CL_int

d. CL_H = Q_H

a. Force A > > > Force B

b. has low enzyme activity (f_u * CL_int ); blood flow dominates (Q_H)

c. CL_H = f_u * CL_int

Given this image and equation, what can you say about High  E_H drugs? (Select all that apply)

a. Force A < < < Force B

b. has high enzyme activity (f_u * CL_int ) > Q_H

c. CL_H = f_u * CL_int

d. CL_H = Q_H

a. Force A < < < Force B

b. has high enzyme activity (f_u * CL_int ) > Q_H

d. CL_H = Q_H

Which affects Hepatic Plasma Flow (Q_H)?

a. Increased by food

b. Increased by enzyme inducing drugs (i.e. Rifampin, phenobarbital)

c. Decreased by liver disease, dietary deficiencies, & enzyme inhibiting drugs

d. Decreased by disease states (<3 failure, liver disease, propranolol)

a. Increased by food

d. Decreased by disease states (<3 failure, liver disease, propranolol)

Which affects Hepatic Enzyme Activity (CL_int)?

a. Increased by food

b. Increased by enzyme inducing drugs (i.e. Rifampin, phenobarbital)

c. Decreased by liver disease, dietary deficiencies, & enzyme inhibiting drugs

d. Decreased by disease states (<3 failure, liver disease, propranolol)

b. Increased by enzyme inducing drugs (i.e. Rifampin, phenobarbital)

c. Decreased by liver disease, dietary deficiencies, & enzyme inhibiting drugs

Which of the following is false about plasma proteins?

a. synthesized in the liver

b. drugs with higher affinity for the same protein binding site do not displace the drug already on the site

c. albumin is a plasma protein

d. chronic liver disease (cirrhosis) decrease plasma protein concentrations

b. drugs with higher affinity for the same protein binding site do not displace the drug already on the site

False. Aspirin has higher binding affinity so it displaces Warfarin from Albumin.

True or false: For Low E_H, CL_H is affected only by changes of Q_H.

False. Low E_H —> CL_H is affected by changes in CL_int and f_u. 

• Rate-limited by the concentration of unbound drug that enters hepatocytes and metabolic activity

True or false: For High E_H, CL_H is affected only by changes of Q_H.

True! CL_H is rate limited by rate of drug presentation to liver