Principles Of Metabolism And Excretion Flashcards
1
Q
Role of the Liver in Pharmacokinetics
A
- Liver is prime site of drug metabolism
• Ultimate elimination organ
• Responsible for pre-systematic
elimination (First-Pass Effect)
• Most drugs are metabolised in the liver
• Metabolism primarily involves cytochrome P450 enzymes (CYP450), located in hepatocytes
2
Q
What is drug metabolism?
A
- Enzymatic modification of a molecule’s chemical structure
- often targeting xenobiotics but may also involve endogenous molecules.
3
Q
What is the primary purpose of metabolism ?
A
- to make fat soluble chemicals water soluble
• Pathways for excretion generally require water solubility (e.g., urine, bile, faeces)
4
Q
What are two key concepts in drug removal by the liver?
A
- Hepatic Clearance (CLH) and Hepatic Extraction Ratio (EH)
- Drug metabolising enzymes present in almost all tissues but most abundant in liver
5
Q
Why are lipid-soluble drugs poorly excreted in urine?
A
- Lipid-soluble drugs are poorly excreted in urine because they are stored in adipose tissue or circulate until they are converted to water-soluble metabolites.
6
Q
Where are water soluble drugs excreted ?
A
- more readily excreted in the urine.
• May be metabolised, but not generally by CYP enzymes
7
Q
How do drugs administered intravenously (IV), transdermally (TD), or subcutaneously (SC) enter the body?
A
- Drugs administered IV, TD, or SC enter systemic circulation directly, reaching target organs before undergoing hepatic modification.
8
Q
How are oral drugs absorbed and delivered to the liver?
A
- Oral drugs are absorbed in the GI tract and delivered to the liver via the portal vein.
9
Q
What is the first-pass effect?
A
- liver metabolizing drugs before they reach systemic circulation, reducing their bioavailability.
10
Q
What is the bioavailability implication of drugs with extensive first-pass metabolism?
A
- require a larger oral dose than an equivalent IV formulation to achieve the same effect
- as more drug is metabolized in the liver before reaching systemic circulation.
11
Q
What is the bioavailability implication of drugs with low first-pass metabolism?
A
- Drugs with low first-pass effect (theophylline, phenytoin, diazepam) require similar or only slightly higher oral doses compared to when given i.v.
12
Q
Can drugs with no first-pass effect still have low bioavailability?
A
- Yes, drugs with no first-pass effect can still have low bioavailability due to factors like poor absorption, limited solubility, or rapid elimination.
13
Q
Which routes allow drugs to avoid the first-pass effect?
A
- Sublingual and rectal routes allow drugs to bypass the liver’s first-pass metabolism
- leading to more drug reaching systemic circulation.
14
Q
What happens to most metabolic products of drugs?
A
- Most metabolic products of drugs are less pharmacologically active than the parent compound.
15
Q
Important exceptions:
A
- Where the metabolite is more active, such as pro-drugs (e.g. terfenadine)
• Where the metabolite is toxic (e.g. paracetamol)
• Where the metabolite is carcinogenic
16
Q
Why is there a close relationship between drug metabolism and normal biochemical processes in the body?
A
- often involves enzymes and pathways designed for endogenous compounds like steroid hormones, cholesterol, and bile acids
- which can also metabolize drugs that resemble natural substrates.
17
Q
What do Phase I reactions do to a drug?
A
- convert the parent compound into a more polar (hydrophilic) metabolite
- by adding or unmasking functional groups like -OH, -SH, -NH2, -COOH, making it easier for excretion.
18
Q
What is the outcome of Phase II reactions in drug metabolism?
.
A
- involve conjugation with endogenous substrates (e.g. glucuronide, sulfate, acetate, amino acids)
- to increase the drug’s aqueous solubility, often making the metabolite inactive
19
Q
What is the role of Phase III in drug metabolism?
A
- Phase III involves transmembrane transport, where efflux of metabolites, and sometimes the unchanged parent drug, occurs to remove substances from the cells.
20
Q
What is the role of Phase III in drug metabolism?
A
- Phase III involves transmembrane transport, where efflux of metabolites, and sometimes the unchanged parent drug, occurs to remove substances from the cells.
21
Q
What happens during oxidation reactions in drug metabolism?
A
- oxygen is incorporated into the drug, often leading to the loss of part of the drug and making it more polar for easier excretion.
22
Q
What enzyme system is primarily responsible for oxidation reactions in drug metabolism?
A
- The Cytochrome P450 enzyme
23
Q
Phase II Reactions
A
• Glucuronidation by UDP-Glucuronosyltransferase:(-OH, -COOH, -NH2, SH)
24
Q
What is elimination ?
A
- Is any process involved in the excretionof drugs from the body/ removal of drugs from the body
25
What is elimination ?
- Is any process involved in the excretionof drugs from the body/ removal of drugs from the body
26
What are some minor elimination routes for drugs?
- exhalation (for anesthetic gases),
- sweat,
- saliva
- breast milk
27
Major elimination routes
- Kidney
• Liver
28
How does excretion occur through lungs kidney and liver ?
- Kidney = Excretion via urine
- Liver = Excretion via bile (faeces)
- Lung = Excretion via air
29
What is the role of filtration in renal drug elimination?
- Filtration in the kidneys allows only free (unbound) drugs to pass through the Bowman’s capsule
- meaning albumin-bound drugs cannot be filtered
- If albumin can be measured in the urine -> indicator for kidney disease
30
How does reabsorption affect drug elimination in the kidneys?
- Usually substances like glucose and amino acids are reabsorbed
• No hydrophilic drugs get reabsorbed whereas lipophilic drugs do
• Metabolism makes a drug more water-soluble to prevent reabsorption
• A change in pH and charge prevent reabsorption (= ion trapping)
31
4 stages of renal drug elimination
- filtration
- reabsorption
- secretion
- excretion
32
What is CLrenal ?
- Renal clearance is the volume of plasma per unit time that gets filtered of a drug
• Unit: volume over time (mL/min) or (L/h)
- CLrenal does not provide information about the amount of drug cleared
- but the rate of elimination (ROE) indicates how much drug is eliminated
33
What is the equation for ROE ?
- ROE (mg/min) = CLrenal × C, where C is the plasma concentration of the drug
34
Two terms that are very closely associated with CLrenal are….
- Glomerular Filtration Rate (GFR)
• Creatinine Clearance (CLcreatinine)
35
How does lower GFR affect ROE ?
- GFR is an indicator of kidney function, and a lower GFR means less drug is eliminated (↓ ROE)
36
What is biliary excretion ?
- Excretion through the faeces
37
What is Biliary secretion ?
- active secretion of endogenous and exogenous
drugs/substances from the hepatocytes in to the bile and duodenum
38
Pharmacokinetic Half-life
- Half-life is individual and constant for each drug
- Follows first order elimination rate
- Half-life time determines the dose and the dosing interval
- >95% of the drug is excreted always after 5 half-life times (t1/2)
39
Phase I reactions
- Oxidation
