Kinetics Final Exam

Pharmacogenetics

the study of genetic differences responsible for differences in drug elimination and responses to drug

For a given drug, what two things may be variable between species?

Rate and or pathway of biotransformation

Drug elimination =

drug excretion + drug metabolism

Where is the main site of drug metabolism (biotransformation)?

Liver

Phase I

in which a functional group is introduced or exposed

Phase II

in which a polar moiety gets appended to drug

Phase III

transporter

What are examples of prodrugs?

1. Prednisone

2. Cortisone

Prodrug

a drug not in its active form (requires metabolism)

True or False: Drugs may not be designed to increase systemic absorption?

False

What does phase I usually do?

Inactives drug

What can Phase I ester / amide hydrolysis do?

activate prodrugs and toxicants

What does Phase I add / exposes?

1. Oxygen (hydroxyl, epoxide groups)

2. Sulfur

3. Nitrogen - acceptor site for hydrophilic moieties

What does Phase II improve?

water solubility (hastens elimination in urine and bile)

What does Phase II inactive?

electrophilic and toxic oxidized metabolites

During Phase III the drug transporter phase, what is there an influx of?

1. nutrients

2. ions

During Phase III the drug transporter phase, what is there an efflux of?

1. Waste

2. Toxins

3. Drugs

4. Xenobiotics

In Phase III the drug transporter phase, what are absorption and elimination?

1. Intestinal

2. Renal

3. Hepatic

In Phase III the drug transporter phase, what are protective barriers?

1. Brain

2. Testes

In Phase III the drug transporter phase, what are the drug resistance?

1. Anticancer

2. Antiviral

3. Anticonvulsant

What are factors that affect drug metabolism?

1. Age

2. Disease

3. Specific differences

4. Heredity / Genetics

5. Gender

6. Pregnancy

7. Environmental Factors

8. Drug Dose

9. Enzyme induction

10. Enzyme inhibition

11. Diet, Nutrition

ATP Binding Cassette (ABC) transporters

efflux transporters

Solute Carrier (SLC) transporters

Can be efflux of influx transporters

What is Hepatic Clearance of Drugs defined as?

the volume of liver-perfusing blood that gets cleared of a drug per unit time

What is an example that has High ER?

propranolol

True or False: A drug like propranolol that has a high ER will change in blood flow influence the rate of metabolism

True

Auto-induction

makes its own metabolism more active

What are examples of drugs that have an adaptive process?

1. Phenobarbital

2. Metabolic tolerance

CYP3A4

many inhibitors, substrates

CYP2D6

Highly variable, many substrates

Intrinsic clearance (CLint)

is a measure of the inherent capacity of the liver to metabolize a drug in the absence of flow limitations

Drugs / food inhibit what?

CYP450s

CLt =

CLr + CLnr

How are many drugs cleared by the liver?

Restrictively

What drugs are removed non-restrictively from the liver?

1. Propanolol

2. Morphine

True or False: When a restrictively cleared drug is displaced from plasma protein blinding, clearance increases

True

If drugs that are non-restrictively removed what does that mean?

ER > fu (the fraction of unbound drug)

Low intrinsic means

that it restrictively cleared

For drugs with high intrinsic clearance ClH is ____________ of protein binding and _______ on hepatic blood flow

indenpendent, dependent

First pass effect

orally administered drugs get rapidly metabolized extensively by the intestinal mucosal cells and the liver before entry into the general circulation

Before enzyme saturation, metabolism is a

first order process

Upon saturation, metabolism is a

zero order process

Drugs that have a high ER have what and why?

A poor bioavailability when administer orally because of the first pass effect

Drugs that dissolve slowly when administered by mouth are more susceptible to?

First pass effect

How do you overcome first pass effect?

1. Change route of administration

2. Increase oral dose

3. Use a more rapidly absorbable formulation

Competitive Inhibition

drug and inhibitor compete for the same active site on enzyme. change in Km but Vmax is unchanged

Non-competitive Inhibition

inhibitor acts at a site other than active enzyme site. Km is the same but Vmax is lower

Uncompetitive Inhibition

inhibitor combines only the drug-enzyme complex

True or False: If a drug is given orally, it is more likely to be excreted in bile than if it is given IV

True

If the molecular weight is less than 300 how is it excreted?

Renal only

If the molecular weight is between 300 and 500 how is it excreted?

Bile and kidney

If the molecular weight is larger than 500 how is it excreted?

Bile only