Drug Disposition and Metabolism

Question 1

Describe the importance of metabolism from a drug therapy perspective

Answer 1

Aids in elimination of drugs from the body (increased clearance, decreased plasma half life for many drugs)
Acts to limit absorption of orally administered drugs

Question 2

What are the basic principles of drug metabolism?

Answer 2

Metabolism often removes biological activity, but can also result in active drug
Most metabolism follows first-order kinetics; rate of loss is proportional to concentration in plasma
First order enzyme kinetics takes approximately 5 half lives to essentially remove the drug from the body (however some drugs can be stored in fat cells for a longer period of time)

Question 3

What is the first pass effect?

Answer 3

Oral drugs are absorbed through the duodenum, and travel through the hepatic portal vein to the liver, where metabolism begins before the drug makes it to the bloodstream

Question 4

What are the key points of drug metabolism?

Answer 4

Most drugs are metabolized before being eliminated from the body
Drug metabolites are usually more polar than their parent compound
The expression of drug metabolizing enzymes differs among tissue type
Ingestion of 2 or more drugs can affect the rate of metabolism in one or both drugs

Question 5

How are the drug metabolism reactions divided?

Answer 5

Phase 1 reactions - drug is modified (oxidation, reduction, hydrolysis)
Phase 2 reactions - drug is inactivated (glucurondiation, sulfation, acetylation)

Question 6

What are the stages of drug transformation

Answer 6

Absorption, Metabolism (phase I, phase II) and elimination

Question 7

What is the order of the phases?

Answer 7

There is more than one path:
Phase I then phase II
Just phase I
Just phase II
Neither phase
Phase I, then phase II then phase I again

Question 8

What are example of phase II reactions?

Answer 8

Glucuronidation (carboxylic acid, alcohol, phenol, amine)
Amino acids (carboxylic acids)
Acetylation (amines)
Sulfation (alcohol, phenol, amine)
Glutathione conjugation (halo-cpds, epoxides, arene oxides, quinone-imine)

Question 9

What are the therapeutic consequences of phase I and phase II metabolism?

Answer 9

Accelerated renal excretion
Drug inactivation (particularly phase I)
Activation of prodrugs
Decreased toxicity
Increased therapeutic action
Increased toxicity

Question 10

What are the hepatic drug metabolizing enzymes?

Answer 10

Drug metabolism is performed by microsomal enzyme system aka P450 system

Question 11

Describe the P450 system

Answer 11

It consists of 12 families
3 of these families metabolize drugs (CYP 1, 2, 3)
9 of these families metabolize steroids and fatty acids, etc.

Question 12

What is the most important drug metabolizing enzyme?

Answer 12

CYP3A4

CYP3A5

Question 13

What are the four essential constituents for P450 drug oxidation?

Answer 13

NADPH
Molecular oxygen
P450 reductase (flavoprotein)
P450 enzyme (heme protein)

Question 14

What are examples of CYP3A4 substrates?

Answer 14

Acetaminophen
Cocaine
Testosterone

Question 15

What are examples of CYP3A4 inducers? What can inducers do?

Answer 15

St. John’s Wort
Inducers can induce expression of CYP3A4, which can increase the rate of metabolism of CYP3A4 substrates, leading to a decrease in effect

Question 16

What are examples of CYP3A4 inhibitors? What can inhibitors do?

Answer 16

Grapefruit juice
Inhibitors inhibit the expression of CYP3A4, which can decrease the rate of metabolism CYP3A4 substrates, leading to an increase in effect

Question 17

How do enzymes induce the expression CYP enzymes

Answer 17

The mechanism involves the binding of the drug to a site on the gene encoding the enzyme. This increases the synthesis of the enzyme

Question 18

What are examples of enzyme induction?

Answer 18

Phenytoin is an anticonvulsant medication, which over time causes an increase in expression level for various CYP450 enzymes (CYP3A4)
Rifampicin is an antimicrobial agent that induces CYP450 expression

Question 19

Why is induction important?

Answer 19

The mechanisms allows enzymes to change in response to a xenobiotic. It’s a dynamic system that can respond to the environment.
From a drug stand point, it can affect the pharmacokinetics (increased clearance, decreased half life, etc) and pharmacodynamics (decrease response, etc.)

Question 20

The induction of enzymes is not only a drug interaction phenomenon. Explain.

Answer 20

Induction can be affected by the environment or the patient’s lifestyle (smoking, etc.)
Herbal and nutritional supplements also affect induction

Question 21

What are different types of drug interactions?

Answer 21

Enzyme inhibitors
Enzyme inducers
Drug A blocks metabolism of drug B
Drug A increases the amount of enzyme for metabolism
Pharmacodynamics: increased/decreased response
Pharmacokinetics: increase/decreased plasma half life
Effects are immediate
Effects are delayed

Question 22

What are some general examples of inducers?

Answer 22

Ethanol
Omeprazole
Phenobarbital
Rifampin
Smoking

Question 23

What are some general examples of inhibitors?

Answer 23

Cimetidine
Erythromycin
Grapefruit juice
Ketoconazole
Quinidine

Question 24

Explain how cimetidine is an enzyme inhibitor

Answer 24

Cimetidine is an H2 receptor antagonist, used to treat peptic ulcers
It is a potent inhibitor of several different CYP450 enzymes
Drug interactions include warfarin, benzodiazepines, phenytoin, morphine
PK effects: decreased clearance, increased half life
PD effects: increased response, increased duration

Question 25

How can genetic variability affect the CYP gene family?

Answer 25

It can affect expression levels, enzyme activity, enzyme induction
In general: different phenotypes can affect a patient’s response to drugs. This has implications on the importance of personalized medicine