Metabolism/Pharmacokinetics

Question 1

Drug metabolism

Answer 1

biochemical modification of pharmaceutical substances by living organisms usually through specialised enzymatic activity

Question 2

What is metabolism?

Answer 2

-an essential pharmacokinetic process, which limits the life of a substance in the body, by rendering lipid soluble and non-polar compounds to water soluble and polar compounds so that they can be excreted.

Question 3

Why does metabolism occur?

Answer 3

only water-soluble substances undergo excretion whereas lipid soluble substances are passively reabsorbed from renal or extra renal excretory sites back into the blood

Question 4

Where are the important sites of metabolism?

Answer 4

• liver
• gut lining
• kidneys
• lungs

Question 5

What are the effects of metabolism?

Answer 5

• loss of pharmacological activity
• decrease in activity with metabolites that show some activity
• increase in activity, more active metabolites
• production of toxic metabolites

Question 6

Describe metabolising enzymes.

Answer 6

• wide substrate specificity
• individual drugs can be metabolised by more than 1
• enzyme activity is regulated at several levels
• some enzymes are expressed constitutively
• others are expressed or induced in the presence of a particular substrate

Question 7

What are the 3 reactions that phase 1 metabolism can involve?

Answer 7

• hydrolysis
• oxidation
• reduction

Question 8

What does phase 1 do?

Answer 8

increases the polarity of the compound and provides an active site for phase 2 metabolism

Question 9

What family of enzymes are the most important metabolising enzymes?

Answer 9

cytochrome P450

Question 10

How is drug specificity determined?

Answer 10

by the isoform of the cytochrome P450

Question 11

What is CYP3A4?

Answer 11

• the major constitutive enzyme in human liver and contributes to the metabolism of a wide range of drugs.
• also found in the gut and is responsible for the pre-systemic metabolism of drugs such as diazepam, methadone, simvastatin, CCBs

Question 12

What is CYP2D6?

Answer 12

• responsible for the metabolism of some antidepressants, antipsychotics and the conversion of codeine to morphine
• induced by cigarette smoke

Question 13

What is CYP1A2?

Answer 13

• important in the role of metabolism of theophylline

- induced by smoking

Question 14

What does Phase 2 involve?

Answer 14

-conjugation

Question 15

What is conjugation?

Answer 15

• Conjugation increases the water solubility and enhances excretion of the metabolised compound.
• Conjugation involves the attachment of glucuronic acid, glutathione, sulphate or acetate to the metabolite generated by phase 1.
• conjugation usually results in inactivation however, a small number of drug metabolites may be active.

Question 16

What happens during phase 2 metabolism?

Answer 16

a molecule endogenous to the body donates a portion of itself to the foreign molecule

Question 17

What factors affect metabolism?

Answer 17

• other drugs, herbals, natural substances
• genetics
• hepatic blood flow
• liver disease
• age
• sex
• ethnicity
• pregnancy

Question 18

What does induction of an enzyme involve?

Answer 18

increased synthesis and therefore increased activity

Question 19

What can result from genetic variation- pharmacogenetics?

Answer 19

variation in response to drugs can result in therapeutic failure or ADR.

Question 20

Why are inter-individual differences in gene expression common?

Answer 20

• drug metabolising enzymes are often expressed in multiple forms
• gene mutations can also occur resulting in deficiencies or absence of a particular metabolising enzyme

Question 21

What does lack or decreased activity of an enzyme often result in?

Answer 21

• drug toxicity

- less commonly, enhanced metabolism, reduced drug effect, drug resistance

Question 22

What are the 4 phenotype subpopulations of metabolizers known?

Answer 22

• poor metabolisers PM
• intermediate metabolisers IM
• extensive metabolisers EM
• ultrarapid metabolisers UM

Question 23

What does CYP2C9 do?

Answer 23

metabolises 16 commonly used drugs including warfarin and phenytoin

Question 24

What is known about CYP2C 19?

Answer 24

there are 8 allelic variants all are non-functional proteins

Question 25

What enzymes exhibit genetic variation?

Answer 25

• pseudocholinesterase
• N-acetyltransferase
• cytochrome P450 2D6
• cytochrome P450 2C19
• TMPT

Question 26

Describe metabolism in fetus/premature infants

Answer 26

-drug metabolising enzymes deficient/reduced
-renal function deficient
metabolites

Question 27

What is the rate of metabolism in toddlers?

Answer 27

metabolise drugs more rapidly than adults

Question 28

What is the rate of metabolism by puberty?

Answer 28

metabolise drugs greater than adults

Question 29

In what way does metabolism differ for men and women?

Answer 29

In response to certain drugs

Question 30

How does pregnancy affect drug metabolism?

Answer 30

Induction of certain drug metabolising enzymes occurs in second and third trimester

Question 31

What kind of effect do hormonal changes during development have?

Answer 31

Profound effect

Question 32

What happens in the elderly?

Answer 32

parameters such as plasma protein, lean body mass and liver weight decrease significantly and so alter drug metabolism

Question 33

Why might race affect metabolism?

Answer 33

There are many incidences in the genetic expression of cytochrome P450 isoforms