What is the main route of drug elimination?
Most drugs are eliminated via urine, either unchanged or as polar metabolites.
What are other routes of drug elimination?
Bile (to intestine), lungs, sweat, and milk.
Why are lipophilic drugs not efficiently excreted by kidneys?
Because they are reabsorbed by diffusion; metabolism converts them into polar compounds for excretion.
What is drug metabolism?
The enzymatic conversion of drugs into metabolites, usually making them more polar for easier elimination.
Where does most drug metabolism occur?
In the liver, primarily via cytochrome P450 enzymes embedded in the endoplasmic reticulum.
What are the two main phases of metabolism?
Phase I (functionalization reactions by P450 enzymes) and Phase II (conjugation reactions).
What typically happens during Phase I reactions?
A reactive group, such as hydroxyl (-OH), is introduced into the molecule.
What typically happens during Phase II reactions?
A substituent such as glucuronide is attached to the molecule, increasing water solubility for excretion.
What does the P450 enzyme contain?
A ferric iron (Fe3+) center that binds to the drug (DH) and activates molecular oxygen to oxidize the drug.
What cofactor donates electrons in the P450 cycle?
NADPH-P450 reductase.
What is the product of P450 metabolism?
A hydroxylated product (DOH) that can undergo conjugation.
What enzyme performs glucuronidation in Phase II?
UDP-glucuronyl transferase.
List the main P450 families and their notable drugs.
CYP1: Theophylline, caffeine, paracetamol; CYP2: ibuprofen, phenytoin, warfarin, omeprazole; CYP3: ciclosporin, nifedipine, losartan.
Which enzyme metabolizes alcohol?
CYP2E1.
Which enzyme metabolizes warfarin and ibuprofen?
CYP2C9.
Which enzyme metabolizes codeine and metoprolol?
CYP2D6.
Which enzyme metabolizes ciclosporin and nifedipine?
CYP3A4/5.
What causes genetic variation in P450 activity?
Polymorphisms in genes encoding P450 enzymes leading to slow or fast metabolism.
Give examples of environmental influences on P450 enzymes.
Grapefruit juice inhibits metabolism; Brussels sprouts and cigarette smoke induce P450 enzymes.
How does metabolism affect aspirin?
Aspirin is hydrolyzed to salicylic acid, which retains anti-inflammatory but not antiplatelet activity.
What can metabolism produce?
Active metabolites, inactive compounds, or toxic metabolites.
Give an example of metabolism activating a prodrug.
Conversion of codeine to morphine by CYP2D6.
What is the main organ for drug and metabolite elimination?
The kidney.
How much of the drug crosses the glomerular filter?
Approximately 20%.
