Drug metabolism and elimination

Question 1

Sites of metabolism

Answer 1

– Gut lumen – Gut wall
– Plasma
– Lungs
– Kidneys – Nerves – Liver

Question 2

Mixed-function oxidase system (CYP450s)

Answer 2

these are microsomal enzymes (ER) enzymes which are found in the liver, kidney, lung, intestine etc.

consist of:
– cytochome P450
– NAPDH-CYP450 reductase
– lipid

requires:
– molecular oxygen
– NADPH

Question 3

CYP2B6 and efavirenz (antiretroviral)

Answer 3

– CYP2B6 deficient alleles more common in African populations
– Linked to increased systemic exposure and increased risk of
neurological symptoms

Question 4

CYP2C8 and paclitaxel (chemotherapy)

Answer 4

– CYP2C8 deficient alleles more common in African and European populations
– Linked to increased risk of drug-induced neuropathies

Question 5

CYP2D6 and tricyclic anti-depressants

Answer 5

– Polymorphisms in CYP2D6 overactivity more common in African populations
– Leads to decreased treatment response

Question 6

Potential for competition and saturation

Answer 6

– drugs and endogenous compounds for same enzyme – different enzymes for same substrate
– enzyme can be saturated, conjugate depleted

Question 7

Issues of variation/induction/inhibition

Answer 7

– inter-individual responses can vary

– substantial issue due to broad specificity of enzymes

Question 8

factors that effect metabolism

Answer 8

age (elderly it starts to decline and there is a low level of activity in children)
disease (liver function)
other medications  (induction and inhibition of metabolic enzymes)
genetic variation (CYP phenotypes and race)

Question 9

Possible sources of excretion include:

Answer 9

• Breath
• Urine
• Saliva
• Perspiration
• Feces • Milk • Bile
• Hair
The kidneys are the most important organs involved in the elimination of drugs and their metabolites

Question 10

Transfer of drugs from plasma to bile

Answer 10

– Organic cation transporters (OCTs)
– Organic anion transporters (OATs)
– P-glycoproteins (P-GP)

Question 11

Concentrated in bile, delivered to intestine

Answer 11

– Hydrophilic drug conjugates (e.g. glucuronides)
– Hydrolysis of conjugate can occur
• Reabsorption of liberated drug
• Enterohepatic circulation

Question 12

Enterohepatic circulation example

Answer 12

oral antibiotics and oral synthetic oestrogen’s

Question 13

Glomerular filtration

Answer 13

– Filters drugs below 20 kDa in molecular weight

– Not filtered if drug bound to plasma albumin

Question 14

tubular secretion

Answer 14

– OATs and OCTs

– Cleared even if bound to plasma albumin

Question 15

diffusion across renal tubule

Answer 15

– If tubule freely permeable, 99% of drug reabsorbed • Lipophilic drugs excreted poorly
• Polar drugs remain in lumen
– Urinary pH?

Question 16

Weak acids more rapidly excreted if

Answer 16

urine is alkaline

Question 17

Weak bases more rapidly excreted if

Answer 17

urine is acidic

Question 18

Ion trapping

Answer 18

• Moreioniseddrug • Lessabletobe
reabsorbed
• Eliminatedinurine

Question 19

Zero order

Answer 19

– Few drugs
– Constant amount metabolised/unit time
– Does not vary with amount of drug present
– Enzyme saturation

Question 20

First order

Answer 20

– Most drugs
– A constant fraction metabolised/unit time
– Increases proportionately to drug conc.
• Moredrug,moremetabolised

Question 21

Salicylic acid

Answer 21

– Non-linear kinetics

– High doses saturate