metabolism and pharmacokinetics

Question 1

What is drug metabolism?

Answer 1

biochemical modification of pharmaceutical substance by living organisms through specialised enzymatic activity

Question 2

metabolism important factors and purpose

Answer 2

essential process
limits the life of substance in the body
purpose is to increase water solubility of the substance to aid excretion or to deactivate compounds

Question 3

what is a prodrug?

Answer 3

one that is activated following metabolism
or that creates active metabolites
ie codeine or enalapril

Question 4

what are the effects of metabolism on pharmaceutical substances?

Answer 4

loss of pharmacological activity- drug’s life is limited, deactivated

decrease in activity with metabolites that show some activity

increase in activity, more active metabolites (prodrug

production of toxic metabolites (direct toxicity, carcinogenesis, teratogenesis)

Question 5

enzymes:- substrate specificity? expression? regulation?

Answer 5

wide substrate specificity- individual drugs can be metabolised by more than one

enzyme activity control is regulated at several levels

some enzymes are expressed constitutively (at a constant level, indispensable role) others are expressed or induced in the presence of a particular substrate

Question 6

How many phases is metabolism divided into?

Answer 6

2 phases

Question 7

phase 1 metabolism simple

Answer 7

oxidation, reduction and hydrolysis of the drug resulting in activation or inactivation of it

Question 8

phase 2 metabolism simple

Answer 8

glucuronidation

resulting in conjugation products

Question 9

Phase 1 in more depth

Answer 9

polar groups are exposed on or introduced to a molecule increasing the polarity of the compound and provides an active site for phase 2

Question 10

What is the most important super family of metabolising enzymes?

Answer 10

cytochrome P-450 enzymes

Question 11

what is drug specificity for cytochrome P-450 enzymes determined by

Answer 11

the isoform of the cytochrome P-450.

i.e It has a number of isozymes with differing substrate specificity and regulatory
mechanisms.

Question 12

what is cytochrome P-450 responsible for

Answer 12

the majority of drug oxidation

Question 13

what is CYP3A4? and what does it contribute to?

Answer 13

isozyme of cytochrome p450
a major constitutive enzyme (constantly produced) in liver
- metabolism of a wide range of drugs. Also found in the gut and is responsible for pre-systemic metabolism of several drugs (ie before the liver)
drugs like methadone or diazepam

Question 14

Phase 2 in depth

Answer 14

involves conjugation
which involves a phase I metabolite joining to another compound (eg, glucuronic acid, sulfate, glycine)
usually results in inactivation but a small number of drug metabolites may be active

Question 15

what is conjugation?

Answer 15

Phase I metabolite joining to another compound

increases the water solubility and enhances excretion of metabolised compound

Question 16

which factors affect metabolism?

Answer 16

other drugs/herbals (green tea)/natural substances
genetics
hepatic blood flow
liver disease
age
sex
ethnicity
pregnancy

Question 17

factors that may induce drug metabolism

Answer 17

smoking: Enzymes induced by tobacco smoking may also increase the risk of cancer by enhancing the metabolic activation of carcinogens
alcohol

Question 18

What does induction of an enzyme involve? and what are the most common enzyme inducers?

Answer 18

increased synthesis and therefore increased activity- process may take weeks
smoking and alcohol
also drugs like phenytoin- anti seizure (epilepsy)

Question 19

enzyme inhibition

Answer 19

many commonly used drugs, herbal medicines and food stuffs may inhibit drug metabolising enzymes ie cimetidine, grape fruit

Question 20

genetic variation and link to pharmacokinetics?

Answer 20

wide variability in the response to drugs between individuals
consequences of these variations ma be therapeutic failure or adverse drug reaction

Question 21

What can happen if a patient is missing metabolising enzymes?

Answer 21

some drugs could not be inactivated or broken down so they accumulate- highly toxic which could cause damage

Question 22

gender and pharmacokinetics

Answer 22

sex differences have been found in all four pharmacokinetic areas:- Absorption, distribution, metabolism and elimination
responsiveness to a drug is different in men and women

hormonal changes during development have a profound effect on drug metabolism

Question 23

Age children and adolescents + drug metabolism

Answer 23

drug metabolising enzymes are often deficient or reduced in the fetus or premature infant
by the age of 2 years children can metabolise many drugs more rapidly than adults
puberty= highest rate

Question 24

elderly and drug metabolism

Answer 24

levels of plasma protein, lean body mass and liver weight decrease significantly so alter drug metabolism
chronic disease is also more common and so the elderly are likely to be on multiple drug therapy (co-morbidity)

Question 25

racial differences occur in the genetic expression of what

Answer 25

cytochrome P-450 isoforms

Question 26

why is Absorption Distribution Metabolism Excretion (ADME) important?

Answer 26

to determine how to get the drug to its site of action
determining the dose and frequency
making sure the drug is present in an effective dose
predicting and avoiding toxicity
making changes based on other drugs, illness or physiological factors

Question 27

are phase 1 and phase 2 sequential phases

Answer 27

no

a drug may only go through phase 1 or phase 2

Question 28

What is CYP1A2 and what is it induced by

Answer 28

an isoform of cytochrome p450
smoking
important in the metabolism of theophylline.

Question 29

CYP2D6 what is responsible for

Answer 29

metabolism of some antidepressants, antipsychotics and the conversion of codeine to morphine

Question 30

which 3 isoforms of cp450 are important in phase 1

Answer 30

CYP2D6
CYP1A2
CYP3A4