Metabolism - Intro

Question 1

How is metronidazole metabolised? How does metronidazole affect metabolism?

Answer 1

metronidazole is metabolised by CYP450 (hepatic enzyme)
- dose is reduced in serious liver disease

metronidazole inhibits acetaldehyde dehydrogenase
- acts like disulfiram which treats alcohol addiction
= causes stomach pain, nausea
- avoid alcohol

metronidazole inhibits CYP450
- affects metabolism of other drugs including warfarin and phenytoin

Question 2

What is bioavailability? What are the factors affecting it?

Answer 2

The fraction of an orally administered dose that reaches the systemic circulation as intact drug

affected by
- absorption
- local metabolic degradation

Question 3

What are the types of transport for substances in the body?

Answer 3

passive diffusion - drug moves according to a concentration gradient, moves from an area of high concentration to one of low concentration

carrier mediated transport - active or facilitated diffusion via receptors

paracellular transport - passage between cells, through intracellular spaces

transcellular transport - passage through cells, across the epithelial

drug efflux - occurs via P-gp (P-glycoprotein), effluxes substances outside the cell

intestinal metabolism

organic anion transport protein (OATP) - transporter proteins that regulate anion balance in the body

Question 4

What is metabolism? What is its purpose?

Answer 4

metabolism is an enzymatic process in which drugs and other xenobiotics are converted into more hydrophilic metabolites
- enables elimination and termination of activity

Question 5

What is the main function of the liver?

Answer 5

the liver is the major organ of drug/toxin metabolism

Question 6

What is phase I metabolism?

Answer 6

conversion of the drug and xenobiotic into a more polar metabolite
- by introducing or unmasking a functional group
= OH, NH2 or SH

most frequent reactions are reduction, oxidation and hydroxylation

reactions are catalysed by CYP450s

Question 7

What is phase II metabolism?

Answer 7

reaction that follows phase I metabolism
- formation of a covalent linkage between a functional group on the parent compound/phase I metabolite and an endogenous substrate
= product is highly polar

common groups involved are
- glucuronyl, sulphate, methyl, acetyl, glycol and glutamyl

Question 8

What are the factors influencing drug metabolism?

Answer 8

food/drug interaction
- enzyme induction and inhibition

age
genetic factors
- polymorphism

systemic pathological processes
- liver disease, heart failure

sex
body temperature
species

Question 9

What are enzyme inducers? What are examples of enzyme inducers?

Answer 9

inducers increase enzyme activity can decrease drug potency

barbiturates (phenobarbital), carbamazepine, ethanol (chronic use), glutethimide, griseofulvin. phenytoin, meprobamate, rifampicin and sulphinpyrazone

Question 10

How is paracetamol metabolised?

Answer 10

conjugation with glucuronic acid (45-55%)
conjugation with sulphuric acid (20-30%)

oxidation by CYP2E1
- forms N-acetyl-p-benzo-quinone imine (NAPQI)
= toxic metabolite

Question 11

What are enzyme inhibitors? What are examples of enzyme inhibitors?

Answer 11

enzyme inhibition can slow down the metabolism
- action of co-administrated drug may be increased and prolonged

cimetidine, erythromycin, quinolone, doxorubicin, ethinyloestradiol, atorvastatin, warfarin, tamoxifen, grapefruit juice, sodium valproate and allopurinol

Question 12

How does St John’s Wort affect metabolism?

Answer 12

St John’s Wort induces CYP3A4
- increases cyclosporine elimination
= is an issue in transplant rejection as cyclosporine is an immunosuppressant

enzyme inducer

Question 13

How does grapefruit juice affect metabolism?

Answer 13

Grapefruit juice inhibits CYP3A4
- delays cyclosporine elimination
= leads to cyclosporine nephrotoxicity

occurs via the furancoumarin found in grapefruit juice

Question 14

How is paracetamol overdose reversed?

Answer 14

1) glutathione
- conjugation with glutathione detoxifies NAPQI into non-toxic cysteine and mercapturic acid conjugates

2) N-acetylcysteine (NAC)
- replenishes glutathione by providing cysteine
= cysteine is a precursor in glutathione production

• can directly bind to NAPQI and enhance non-toxic sulphate conjugate
• binds to toxic metabolites and scavenges free radicals

Question 15

How is paracetamol affected by alcohol and phenobarbital?

Answer 15

alcohol
- increases the activity of CYP2E1 making paracetamol toxic even at low doses

phenobarbital
- suppresses glucuronidation resulting in paracetamol production being diverted to NAPQI production

Question 16

How does grapefruit juice affect aliskiren and bilastine metabolism?

Answer 16

grapefruit juice reduces aliskiren and bilastine
metabolism and bioavailability
- inhibits organic anion transport protein (OATP) which these drugs are substrates for
= leads to reduced absorption

Question 17

How does age affect metabolism?

Answer 17

foetal/neonates - UGT expression is reduced and not achieved until 24 months

children under 1 yr - microsomal enzyme system is not fully developed

children - have limited liver ability until 10-12 yrs

elderly - have reduced liver size, hepatic blood flow and enzyme activity (slow metabolism)
= multi-therapy can exacerbate this interaction issue

Question 18

How genetic polymorphism affect metabolism?

Answer 18

variations in genes/DNA sequences can lead to differences in expression of CYP450s
- polymorphism in acetylation
- poor oxidisers
- glucose-6-phosphate-dehydrogenase (G-6-PD) deficiency

Question 19

Why is systemic bioavailability of felodipine less than 100%?

Why is peak plasma levels and bioavailability of felodipine increased with grapefruit juice?

What dose related adverse effect may result from felodipine/grapefruit interaction?

Answer 19

felodipine undergoes first pass metabolism
- metabolised by cytochromes in small intestine enterocytes
- second metabolism by hepatic cytochromes

furancoumarin in grapefruit juice inhibits hepatic CYP3A3
- felodipine metabolism and bioavailability is reduced

hypotension and peripheral oedema
- felodipine is a calcium channel blocker