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MD3002 > Drug Metabolism and Distribution > Flashcards

Drug Metabolism and Distribution Flashcards

1
Q

Identify the main sites of metabolism in the body.

A 
– Gut lumen (physical and chemical barriers, e.g. acidity)
– Gut wall (enzymes)
– Plasma (plasma cholinesterases)
– Lungs
– Kidneys 
– Nerves 
– Liver
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2
Q

What is the main site of drug metabolism ?

A

Liver

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3
Q

Identify the main stages of drug metabolism.

A

Phase I metabolism
• Generally oxidation, reduction or hydrolysis – Introduce/reveal a reactive chemical group
– “Functionalisation”
• Products often more reactive
‹
Phase II metabolism (true detoxification pathway)
• Synthetic, conjugative reactions
• Detoxified, hydrophilic, inactive, easily secreted compounds generated (usually) (Suitable for excretion in bile or urine)

Some will undergo phase 1, some will only undergo phase 2. In general, not necessarily phase 1 then phase II (but Phase I predominately prepares drugs for Phase II metabolism)

Drugs that take the conjugate —> intestines route are vulnerable to deconjugation. Bacterial environment in GI tract can reverse phase II process (deconjugation) and cause re-uptake (liberates the drug)
Drugs that undergo this process have a long half life

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4
Q

Identify the main reactions involved in phase I.

A 
Oxidation (MAINLY)
Reduction
Hydrolysis
Hydration 
Dethioacetylation
Isomerisation
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5
Q

Identify the main reactions involved in phase II (and the associated enzymes).

A

Glucuronidation (UDP-glucuronyltransferase)
Glucosidation (UDP-glycosyltransferase)
Sulfation (Sulfotransferase)
Methylation (Methyltransferase)
Acetylation (Acetyltransferase)
Glutathione conjugation (Glutathione-S-transferase)

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6
Q

What are the main functional groups which are introduced or unmasked by phase I metabolism ?

A

–OH, -NH2, -SH, -COOH

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7
Q

Identify the main oxidation reactions which occur in phase I metabolism.

A

– Mixed-function oxidase system (cytochrome P450)
– Alcohol dehydrogenase (no requirement for phase II metabolism following this)
– Xanthine oxidase

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8
Q

Identify the main reduction reactions which occur in phase I metabolism.

A

– Ketone reduction
– Anaerobic cytochrome P450 metabolism (if no oxygen available, changes from oxidative system into this, and generates different profiles of metabolites, often more toxic)

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9
Q

Identify the main hydrolysis reactions which occur in phase I metabolism.

A

– Ester hydrolysis (e.g. cholinesterases)

– Amide hydrolysis

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10
Q

What are the main components of the mixed-function oxidase system (CYP450s) ? What are its main requirements ?

A

Consists of:
– cytochome P450 (microsomal enzymes in liver, kidney, lung, intestine)
– NAPDH-CYP450 reductase
– lipid

Requires:
– molecular oxygen (otherwise start undertaking reduction reactions)
– NADPH

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11
Q

How many genes code for CYP450 ?

A

Many different genes code for CYP450 (different kinds of CYP450)

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12
Q

How specific are CYP450s to a certain drug ?

A

Some drugs may be metabolised by many CYP450, some

may be preferentially by 1 or 2

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13
Q

Can a drug be a substrate for more than one phase II metabolism reaction ?

A

Drug can be substrate for numerous phase II enzymes (and thus reactions). In other words, overlapping substrate specificities since the same substrate can be used by different enzymes for the reaction they are responsible for.

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14
Q

Describe metabolism and excretion of aspirin.

A

METABOLISM
Aspirin is converted into salicylic acid via phase I metabolism (hydrolysis reaction, introducing/revealing OH group).
(conversion of aspirin into salicylic can also occur spontaneously via oxidation in plasma, without enzyme)

Salicylic acid can then itself undergo oxidation (phase I metabolism) (minority of salicylic acid follows this pathway), or it can undergo glucoronidation (phase II metabolism) (either on OH group introduced by phase I metabolism, or on carboxyl group already present on aspirin already) or Glycination (phase II metabolism).
Most of the salicylic acid undergoes phase II metabolism.

EXCRETION
Aspirin excreted as salicylic acid in urine (after glycinated) or in feces (after glucoronidation).

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15
Q

Describe issues of saturation and competition in metabolism.

A

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

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16
Q

Describe issues of variation/induction/inhibition in metabolism.

A

Issues of variation/induction/inhibition
– inter-individual responses can vary
– substantial issue due to broad specificity of enzymes

17
Q

How are drugs eliminated ?

A

Drugs are eliminated either unchanged or as metabolites

• In general, hydrophilic drugs eliminated more readily than lipophilic drugs

18
Q

Identify possible sources of excretion. Which of these is the most important ?

A
  • Breath
  • Urine
  • Saliva
  • Perspiration
  • Feces
  • Milk
  • Bile
  • Hair
19
Q

Which organ is the most important organ involved in the elimination of drugs and their metabolites ?

A

Kidney

20
Q

Describe the process of biliary excretion of drugs.

A

I- Transfer of drugs from plasma to bile, using one of three transport mechanisms:
– Organic cation transporters (OCTs)
– Organic anion transporters (OATs)
– P-glycoproteins (P-GP) (broad substrate specificity)

II- Concentrated in bile, delivered to intestine
– Hydrophilic drug conjugates (e.g. glucuronides)
– Hydrolysis of conjugate can occur
• Reabsorption of liberated drug
• Enterohepatic circulation

21
Q

Describe what happens in enterohepatic circulation.

A

Drug in intestine → Drug in blood → (Renal Excretion or) Conjugate in liver → Conjugate in bile → Conjugate in intestines → (Excretion in feces or) Drug back in intestine, having been deconjugated

22
Q

Identify examples of drugs for which the enterohepatic circulation is significant. Why ?

A

Oral antibiotics and oral synthetic oestrogens

Antibiotics destroy gut microbiota which normally facilitates enterohepatic circulation. This means that certain oral contraceptives have diminishing effectiveness when taken antibiotics oral (recirculation of synthetic estrogens is impaired, leading to possible problem with unwanted pregnancy).

23
Q

Describe renal excretion.

A

Glomerular filtration
– Filters drugs below 20 kDa in molecular weight
– Not filtered if drug bound to plasma albumin

Tubular secretion
– OATs and OCTs (actively chuck out portion of drug that is not bound to albumin/protein, which shifts eq and leeches more of that drug off of the proteins)
– Cleared even if bound to plasma albumin

Diffusion across renal tubule
– If tubule freely permeable, 99% of drug reabsorbed
• Lipophilic drugs excreted poorly (can readily pass into the CT but also readily pass back into circulation, passively reabsorbed in Proximal and Distal tubule)
• Polar drugs remain in lumen (excreted by passive diffusion process (or via active secretion mechanisms), and unless right chemical properties, will not be reabsorbed)

URINARY PH IMPACTS RENAL EXCRETION

24
Q

Describe the importance of urinary pH in renal excretion.

A

Urinary pH impacts on ionisation:

  • Weak acids (e.g. salicylate) more rapidly excreted if urine is alkaline (because weak acids in alkaline environment will try to donate a proton(ionised))
  • Weak bases more rapidly excreted if urine is acidic (vice versa)

This is due to ion trapping, since more ionised drugs (e.g. weak acids in alkaline environment and vice versa) are less able to be reabsorbed, and are therefore eliminated in urine.

25
Q

Draw a graph for excretion of salicylic acid depending on urinary pH.

A

Refer to slide 18.

26
Q

Identify a way of changing urinary pH.

A

Bicarbonate

27
Q

Distinguish between zero and first order kinetics.

A

Zero order
– Few drugs
– Rate of metabolism is constant (e.g. one unit of alcohol per unit time) (not meaningful half life; half life is how long it takes for 50% of drug to be left in body, so can’t calculate meaningful half life if set amount is removed per unit time)
– Does not vary with amount of drug present
– Enzyme saturation
• e.g. Alcohol dehydrogenase

First order
– Most drugs
– A constant fraction metabolised/unit time (meaningful half life) (i.e. more drug, faster metabolism)
– Increases proportionately to drug
– More drug, faster metabolism
28
Q

Graph zero, and first order kinetics.

A

Refer to slides 19 and 20.

29
Q

Identify a drug which neither obeys zero not first order kinetics.

A 
Salicylic acid (in aspiring toxicity, move from first order 
into zero order (meaning saturating enzymes involved in the detoxification and removal of aspirin so shift into zero kinetic profile so slows down how quickly get rid of aspiring from body unless we start trying to restore elimination as talked about previously))

– Non-linear kinetics
– High doses saturate

30
Q

Identify the main pharmacokinetic parameters (first order).

A
  • apparent volume of distribution (Vd)
  • clearance (CL)
  • t1/2
31
Q

State formula and units for Vd.

A

(total amount of drug in the body blood plasma / concentration of drug)

Units: L or L/kg

32
Q

State formula and units for CL.

A

The sum of all routes of elimination for that drug (e.g. metabolism + excretion)

Units: L/h

33
Q

State formula and units for t1/2.

A

t1/2 directly depends on the volume of distribution (Vd) and inversely on the clearance (CL) of drug from the body:

t1/2 = (ln2xVd) / CL

34
Q

Contrast between Pharmacokinetic parameters of aspirin and Salicyclic Acid.

A

ASPIRIN
Volume of distribution (Vd) 10.5 L
Clearance (CL) 39 L/h
t1/2: 0.20 h

SALICYLIC ACID
Volume of distribution (Vd) 11.9 L
Clearance (CL) 3.6 L/h (dose dep.)
t1/2: 20 h

35
Q

Identify factors that can affect drug metabolism.

A

1) AGE
- Fetus: Maternal protection
- Children: Low level of activity
- Elderly: Starts to decline

2) DISEASE
- Dependent on proper liver function: Cirrhosis, hepatitis, cancer
- Adequate essential amino acid supply: Starvation, cancer
- Other disease/conditions: Kidney disease, severe burns

3) GENETIC VARIATION
- Wide range of CYP phenotypes: Rapid, slow, unusual metabolisers
- Race: Inherent generalisable variability

4) OTHER MEDICATIONS
- Induction of metabolic enzymes: Reduced effectiveness of drugs
- Inhibition of metabolic enzymes: Dietary constituents or drugs

36
Q

What is the most important pharmacokinetic parameter to consider ?

A

Clearance

37
Q

Identify possible results of drug metabolism.

A
  • Pharmacological deactivation (of active compound)
  • Pharmacological activation (of prodrugs)
  • Type of pharmacological response (e.g. how interacts with different receptors)
  • No change in pharmacological activity (but may end up with variety of different metabolites)
  • Change in drug uptake
  • Change in drug distribution

MD3002 (95 decks)

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