5. Pharmacokinetics: Drug metabolism & excretion Flashcards
Metabolism
- Major mechanism for drug elimination
- Liver is a major site
- Initial compound → metabolites
Metabolites
- More polar than the parent compound
- Usually terminates pharmacological action & ↑ removal of drug
↑ Polarity
- May lead to a more rapid rate of clearance because of possible secretion by acid or base carriers in kidney
- ↓ Tubular reabsorption
Potency of metabolites
May have higher or lower potencies
- Qualitatively different pharmacological actions
- Toxic, active from inactive pro-drugs
Xenobiotics
Compounds that are ingested and cannot be used as food
- Harmful if they accumulate in cells
- Detoxified by xenobiotic-metabolising enzymes
Biotransformation
The mechanism for drug elimination
Give examples of xenobiotics
- Synthetic drugs
- Natural poisons
- Antibiotics
Give examples of xenobiotic-metabolising enzymes
- Cytochrome P450 oxidase
- UDP-glucuronosyl transferase
- Glutathione S-transferase
Give phase I of xenobiotic-metabolising enzyme action
- Non-synthetic reactions, enzyme catalysed
- Oxidation/reduction
- Hydrolysis
- Introduction of a functional group (e.g OH)
- E.g Cytochrome P450 oxidases
The majority of small-molecule drug metabolism is carried out in the liver by…
Redox enzyme - Cytochrome P450
Give phase II of xenobiotic-metabolising enzyme action
- Synthetic reaction, conjugation reaction
- Combine drug or metabolite with endogenous substance
- Requires a functional group
- Requires energy indirectly for the synthesis of “active carriers”
- E.g Glucuronyl transferase, sulfotransferase, glutathione transferase
Cytochrome P450: Induction
Pharmacologically IMP as major source of drug interactions
- Drug may induce its own metabolism & that of other drugs
Cytochrome P450: Inhibition
Competitive or non-competitive inhibition of CYP450 enzyme activity
- Results in ↓ metabolism of other drugs or endogenous substates
Glucuronyl transferase
Set of enzymes with unique but overlapping specificities that are involved in phase II reactions
- Catalyses conjugation of glucuronic acid to a variety of active centres
- Located in ER
Excretion
Removal from body
- Usually through kidneys or in faeces
- Can also be removed by saliva, sweat, milk, lungs
- Drugs may also be reabsorbed from intestines
Net renal excretion
Result of 3 separate processes:
- Filtration
- Secretion
- Reabsorption
Filtration
Most drugs have low molecular weight & are freely filtered from plasma at the glomerulus
- Serum binding ↓ filtration
Secretion
Proximal tubule has 2 transport systems that may secrete drugs into ultrafiltrate
- Require energy for active transport against conc. gradient
- Site of potential drug interactions
Reabsorption
Reabsorption of un-ionised form of drugs that are weak acids & bases
- By simple passive diffusion
- Rate is determined by:
- Lipid solubility
- pK
- Conc. gradient of drug between urine and plasma
Renal clearance
Measure volume of plasma cleared of drug per unit time
Clearance of a drug excreted by filtration alone (E.g Insulin)
Will have a clearance equal to the GFR
(125-130ml/min)
Clearance of a drug excreted by filtration and complete secretion (E.g Insulin)
Will have a clearance equal to renal plasma clearance (650 ml/min)
Total body clearance (CL)
Clearance due to renal elimination CLr + clearance due to metabolism CLm
- Renal failure: Clearance of drug may be reduced significantly, resulting in higher plasma levels
Hepatic extraction
Occurs because of the liver’s large size and high blood flow
- Extraction ratio is amount of drug removed in liver divided by amount of drug entering organ
First pass effect
Oral → Portal vein → Liver → Systemic circulation
Drug with hepatic extraction ratio of 1 would have…
0% bioavailability
Drug with hepatic extraction ratio of 0.7 would have…
30% bioavailability
In the presence of hepatic disease, drugs with high first-pass extraction…
May reach systemic circulation in amounts higher than normal
- May require dose adjustment
