5: Biotransformation, Pharmacogenomics, Clinical Drug Trials Flashcards
Drug biotransformation
The enzymatic process where once substance is changed to another
General idea for eliminating compounds via biotransformation
Make the compound more polar + sometimes larger
Three consequences of biotransformation of a drug
- Inactivates
- Becomes a different active compound
- Activates a prodrug
First pass effect
Process by which oral drugs undergo extensive biotransformation after absorption prior to entering circulation
Example of a drug that must be given parenterally bc of how much is lost during first pass effect
Morphine
Phase 1 vs 2: which is anabolic and which is catabolic (generally)
Phase 1: catabolic
Phase 2: anabolic
After phase 1 reaction, are substances generally more or less toxic and reactive?
More toxic and reactive
Major enzymes that act in phase 1 reactions
Monooxygenases, cytochrome P450, epoxide hydrolases
What CPY carries out metabolism of 50% of human drugs?**
CYP3A4
Examples of enzyme inducers
Phenobarbital, ethanol, aromatic hydrocarbons like tobacco smoke, rifampin, St. John’s wort
What happens when acetaminophen exceeds therapeutic doses
Glucuronidation and sulfation pathways are saturated -> P450 is more and more important -> hepatic GSH is depleted faster than its regenerated -> toxic metabolites
Risk for poor metabolizers vs ultrafast metabolizers
Poor: accumulation of toxic drug levels
Fast: undertreated
Most common disease-producing enzyme defect of humans
G6PD deficiency
What does G6PD do and what happens when its defective/deficient?
G6PD: produces NADPH -> regenerates glutathione
Without: hemolytic anemia occurs in the presence of oxidants
What happens in a ryanodine receptor mutation with inhalation anesthetics like succ?
Increases Ca in sarcoplasm -> muscle rigidity -> high body temp and rhabdo-> malignant hyperthermia
What CYP acts on S-warfarin, phenytoin, and NSAIDs?
CYP2C9
What does Vitamin K epoxide reductase complex subunit 1 (VKORC1) do?
Is the target of warfarin
Lead compound
Chemical with pharmacological activity whose structure is used as a starting point for chemical mods in order to improve potency, selectivity, or pharmacokinetic parameters
No-effect dose
The max dose at which a specified toxic effect is not seen
Minimum vs median lethal dose
Minimum lethal dose: smallest dose observed to kill an experimental animal
Medial lethal dose: dose that kills about 50% of the animals
Surrogate endpoint
Outcome of therapy that predicts the real goal of therapy without being that actual goal (ex: measuring LDL levels instead of cardiac events)
