Pharmacokinetics II: Metabolism & Elimination Flashcards
What is Drug Metabolism?
A biologically protective mechanism that has evolved to rid the body of exogenous substances (e.g. toxins)
What is Biotransformation?
Chemical modification made by an organism on a chemical compound
What compounds do metabolic enzymes transform drugs into?
Polar, water-soluble compounds
How are metabolised drugs eliminated?
In urine and/or bile
TRUE OR FALSE:
Drug metabolites are generally MORE pharmacologically active?
False.
They are LESS pharmacologically active
What TWO key reactions can drug metabolism be classified into?
- Functionalism
- Conjugation
What is involved in Functionalism?
- Addition of a function group
- Drug is made MORE chemically reactive
- Prepares drug for Phase II reactions
What is involved in Conjugation?
Drug is coupled to a second, relatively large water-soluble molecule that increases the drugs water solubility
What are the FOUR Phase 1 reactions?
- Oxidation
- Reduction
- Hydrolysis
- Hydration
What are the FOUR Phase 2 reactions?
- Glucuronidation
- Sulfation
- Acetylation
- Glutathione Conjugation
Which organ has a HIGH biotransformation capacity?
Liver
Which organ(s) has a MEDIUM biotransformation capacity?
- Lung
- Kidney
- Intestine
Which organ(s) has a LOW biotransformation capacity?
- Skin
- Testes
- Placenta
Which enzyme catalyses Oxidation reactions, and where does it occur?
- Cytochrome P450
- Smooth ER
Which reaction is the main Phase 1 reaction?
Oxidation
Which enzymes are involved in Reduction reactions?
Reductases
Which enzymes are involved in Hydrolysis reactions?
- Esterases
- Amidases
Give TWO examples of drugs that undergo Reduction reactions?
- Warfarin
- Chloral hydrate
Give TWO examples of drugs that undergo Hydrolysis reactions by Esterases?
- Aspirin -> Salicylic Acid
- Procaine -> 4-aminobenzoic acid
Give an example of a drug that undergoes Hydrolysis reaction by Amidases?
Procainamides -> p-aminobenzoic acid
What enzyme is Cytochrome P450 closely associated with in membrane?
NADPH P450 Reductase
How many gene families of CYP450 do humans have?
> 74 different families
Which THREE families of CYP450 are mainly involved in drug metabolism?
1, 2 & 3
Which TWO CYP450 isoforms metabolise paracetamol?
- CYP1A2
- CYP2E1
What is the major Phase 2 reaction?
Glucuronidation
What substance is added during Glucuronidation?
UDP-glucuronic acid (UDPGA)
What enzyme is involved in Glucuronidation?
Glucuronyl Transferases
What is the cell location of Glucuronidation?
Endoplasmic Reticulum
What are FOUR examples of drugs that undergo Glucuronidation?
- Paracetamol
- Morphine
- 4-hydroxyphenytoin
- Salicylic acid
What enzyme is involved in Sulfation reactions?
Sulfotransferases
What is the cell location of Sulfation reactions?
Cytosol
What are TWO examples of drugs that undergo Sulfation?
- Paracetamol
- Tamoxifen
What enzyme is involved in Glutathione Conjugation reactions?
Glutathione - S - Transferases
What are the cell locations of Glutathione Conjugation reactions?
- Cytosol
- Microsomes (ER)
- Mitochondria
Which toxic metabolite of paracetamol is eliminated by conjugation to Glutathione in the liver?
NAPQI
What is First Pass Metabolism, and where does it take place?
- Pre-Systemic Metabolism
- GI tract and Liver
What is an example of a drug that cannot be administered orally due to First Pass Metabolism?
Morphine
What are TWO issues with First Pass Metabolism?
- Larger dose needed
- Individual variation (unpredictable effects)
TRUE OR FALSE:
Drug metabolism frequently results in the formation of pharmacologically active products (metabolites)?
True
What types of drugs are NOT filtered by Glomerular Filtration?
Drugs bound to plasma protein (albumin)
e.g. warfarin - 98% bound to albumin
Which transporters in the proximal tubule select for ACIDIC drugs?
Organic Anion Transporters (OATs)
Which transporters in the proximal tubule select for BASIC drugs?
Organic Cation Transporters (OCTs)
TRUE OR FALSE:
Drugs bound to plasma proteins can be excreted in the proximal tubule?
True
Where does Diffusion and Reabsorption occur?
Distal tubule
What are THREE types of membrane permeable substances?
- Lipid soluble substances
- Unionised drugs
- Some ionised drugs
How does urinary pH affect drug / metabolite excretion?
If compound in filtrate is ionised at pH of tubular fluid, then it is NOT reabsorbed
How is Phenobarbital (weak acid) excreted?
- Ionised at alkaline pH
- Sodium bicarbonate for overdose patients
- INCREASES urinary pH
- INCREASES excretion
How does a high protein diet affect urinary excretion of a WEAK BASE drug?
- DECREASES urinary pH
*INCREASES excretion
How does a high protein diet affect urinary excretion of a WEAK ACID drug?
- DECREASES urinary pH
- DECREASES excretion
Which types of drug molecules are actively transported across the liver epithelial cells and into the bile duct for excretion?
Large drug molecules > 300 Daltons
What is an example of a drug that is eliminated via the biliary system?
Rifampicin
What are the TWO rate constants in Pharmacokinetics?
- Rate of Absorption - Kab
- Rate of Elimination - Kel
What are the characteristics of Intravenous administration?
*Absorption is INSTANTANEOUS
* Rapid distribution
* Only elimination (Kel) needs to be considered
What are the characteristics of Oral administration?
- Absorption is NOT instantaneous
- Plasma concentration rises initially, then declines
- Absorption AND Elimination both occur
What is the shape of the curve in plasma conc. vs time plot after I.V. bolus for FIRST ORDER elimination kinetics?
Exponential decay
What is the shape of the curve in plasma conc. vs time plot after I.V. bolus for ZERO ORDER elimination kinetics?
Linear
What is the shape of the curve in log plasma conc. vs time plot after I.V. bolus for FIRST ORDER elimination kinetics?
Linear
What is the shape of the curve in log plasma conc. vs time plot after I.V. bolus for ZERO ORDER elimination kinetics?
Non-linear
What is the relationship between elimination rate and drug concentration in FIRST ORDER elimination kinetics?
Elimination rate is PROPORTIONAL to drug concentration
What is the relationship between elimination rate and drug concentration in ZERO ORDER elimination kinetics?
Elimination rate SATURATES with higher drug concentration
What is the term for FIRST ORDER kinetics in Clinical Pharmacology?
Linear Kinetics
What is the term for ZERO ORDER kinetics in Clinical Pharmacology?
Non-Linear Kinetics
What is a concern for FIRST ORDER elimination kinetics?
95% of drugs, at therapeutic concentrations
What is a concern for ZERO ORDER elimination kinetics?
Remaining 5% of drugs, and ethanol
