Drug Metabolism and Elimination

Question 1

Sites of Metabolism

Answer 1

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

Question 2

Results of Metabolism

Answer 2

• Pharmacological Deactivation
• Pharmacological Activation
• Type of pharmalogical response
• No change of pharmacological activity
• Change in drug uptake
• Change in drug distribution

Question 3

Phase 1 Metabolism in the Liver

Answer 3

• Phase 1 Metabolism - Generally oxidation, reduction and hydrolysis but can also include hydration, dethioacetylation and isomerisation reactions; introduce or reveal a reactive chemical group. “Functionalisation”. Products are often more reactive. Predominantly prepares drugs for phase 2 metabolism.
• Oxidations - mixed-function oxidase system (cytochrome P450), alcohol dehydrogenase, xanthine oxidase
• Reductions - ketone reduction, anaerobic cytochrome P450 metabolism
• Hydrolysis - ester hydrolysis (e.g. cholinesterases) and amide hydrolysis.

Question 4

Phase 2 Metabolism in the Liver

Answer 4

• Phase 2 Metabolism - Synthetic, conjugative reactions (glucuronidation/glucosidation, sulfation, methylation, acetylation, amino acid conjugation, glutathione conjugation, fatty acid conjugation and condensation reactions). Hydrophilic, inactive compounds generated (usually). Usually ends in faeces or urine. True detoxification pathway.
• Results in detoxified, water-soluble, easily secreted products. Suitable for excretion in bile or urine.

Question 5

Mixed-function Oxidase System (CYP450s)

Answer 5

• Microsomal (ER) enzymes - liver, kidney, lung, intestine etc
• Consists of: cytochrome P450, NAPDH-CYP450 reductase, lipid
• Requires: molecular oxygen, NADPH

Question 6

Examples of CYP Variation on Clinical Outcomes

Answer 6

• CYP2B6 and Efavirenz (antiretroviral) - CYP2B6 deficient alleles more common in African populations and is linked to increased systemic exposure and increased risk of neurological symptoms.
• CYP2D6 and Tricyclic Antidepressants - Polymorphisms in CYP2D6 overactivity more common in African populations. Leads to decreased treatment response.
• Other factors associated with ethnicity can influence treatment outcomes and disease severity (e.g. socio-economic inequalities).

Question 7

CYP2E1 and Alcohol

Answer 7

Alcohol predominantly metabolised by alcohol dehydrogenase but CYP2E1 also is involved. Alcohol highly induces expression of CYP2E1 via transcriptional and post-transcriptional mechanisms. Will result in increased metabolism of substrates therefore, may shorten the half-life of certain medications by increasing their clearance. CYP2E1 metabolism also causes release of reactive oxygen species (ROS), this leads to liver damage and thought to be key mechanism in alcoholic liver disease.

Question 8

Drug Metabolism

Answer 8

• There are many enzymes capable of metabolising drugs due to overlapping substrate specificities and metabolism of endogenous compounds.
• Potential for competition and saturation - drugs and endogenous compounds for same enzyme, different enzymes for same substrate, enzyme can be saturated and conjugate depleted.
• Issues of Variation/Induction/Inhibition - interindividual responses can vary. Substantial issue due to broad specificity of enzymes.

Question 9

Factors that can affect Metabolism

Answer 9

• Age - foetus (maternal protection), children (have low level of activity), elderly (level starts to decline).
• Disease - dependent on proper liver function (cirrhosis, hepatitis, cancer), adequate essential amino acid supply (starvation, cancer), other disease/conditions (kidney disease, severe burns).
• Genetic Variation - Wide range of CYP phenotypes (rapid, slow, unusual metabolisers), race (inherent generalisable variability).
• Other Medications - induction of metabolic enzymes (reduced effectiveness of drugs), inhibition of metabolic enzymes (dietary constituents or drugs)

Question 10

Drug Elimination

Answer 10

• Drugs are eliminated either unchanged or as metabolites. In general, hydrophilic drugs eliminated more readily than lipophilic drugs.
• Possible sources of excretion include: breath, urine, saliva, perspiration, faeces, milk, bile and hair.
• The kidneys are the most important organs involved in the elimination of drugs and their metabolites.

Question 11

Biliary Excretion

Answer 11

• Transfer of drugs from plasma to bile via Organic Cation Transporters (OCTs), Organic Anion Transporters (OATs), and P-glycoproteins (P-GP)
• Concentrated in bile, delivered to intestine. Hydrophilic drug conjugates (e.g. glucuronides). Hydrolysis of conjugate can occur - reabsorption of liberated drug and enterohepatic circulation.

Question 12

Enterohepatic Circulation

Answer 12

Drug in intestine > Drug in blood (can be excreted via kidneys here) > Conjugate in liver > Conjugate in bile > Conjugate in intestine (excretion in faeces) > back to start

Question 13

Renal Excretion

Answer 13

• Glomerular filtration - filters drugs below 20kDa in molecular weight, not filtered if drug bound to plasma albumin.
• Tubular Secretion - OATs and OCTs, cleared even if bound to plasma albumin.
• Diffusion across Renal Tubule - if tubule freely permeable, 99% of drug is reabsorbed. Lipophilic drugs remain excreted poorly and polar drugs remain in lumen. Urinary pH?

Question 14

Excretion of Salicylic Acid

Answer 14

• Weak acids more rapidly excreted if urine is alkaline.
• Weak bases more rapidly excreted if urine is acidic.
• Ion trapping: more ionised drug, less able to be absorbed, eliminated in urine.
• Salicylic Acid - excreted when more alkaline urine pH. Non-linear kinetics. High doses saturate.

Question 15

Zero Order Metabolism

Answer 15

• Few drugs
• Constant amount metabolised/unit time
• Does not vary with amount of drug present
• Enzyme saturation (alcohol dehydrogenase)

Question 16

First Order Metabolism

Answer 16

• Most drugs
• A constant fraction metabolised/unit time
• Increases proportionately to drug concentration (more drug, more metabolised).