Kruse: Intro to Biotransformation, Pharmacogenomics, and Clinical drug trials Flashcards
What kind of metabolite does the phase 1 rxn make?
-usually, a more polar one
What CYP450 enzyme is responsible for most of the phase one rxns?
-CYP3A4
In the slow acetylator phenotype, what enzyme is mutated?
- N acetyltransferase levels
- involved with isoniazid (TB tx)
What are the CYP inducers?
-Phenobarbital, chronic ethanol, aromatic hydrocarbons (smoking), rifampin, St. John’s wort
CYP inhibitors
-Grapefruit juice effect!
What do you give people for acetaminophen overdose?
-N acetyl cysteine
What is the most common disease producing enzyme defect of humans?
- G6PD deficiency
- makes NADPH, which regenerates glutathione from its oxidized form
What is a Lead compund?
-a chemical compund that has pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters
What is no effect dose
-the maximum dose at which a specified toxic effect is not seen
What is minimum lethal dose(LDmin)
-the smallest dose that is observed to kill any experimental animal under a defined set of conditions
What is median lethal dose (LD50)?
-the dose that kills approximately 50% of the animals
What is Phase 0 of clinical trials
- microdoseing of prospective drug candidates are administered to human volunteers
- doesn’t cost much
Phase 1
- determines whether humans and animals show significantly different responses
- usually the first stage in humans
- small number of healthy volunteers
Phase 2
- larger group of pts that have the target disease
- single blind
- this is where drug failure typically occurs
Phase 3
- further establishes drug safety and efficacy of a large groupt of pts
- crossover double blind
- intent is to gather additional info
- most expensive phase
What happens after Phase 3 trials are good to go?
-NDA: new drug application
What is Phase 4?
- after approval to market a new drug
- continues to monitor the safety of the new drug
- no fixed duration
complete phase 1 metabolism will yield what kind of product?
- more polar products
- remember, phase 1, think CYP enzymes
Is glucuronidation a phase 2 or phase 1 rxn?
-phase 2
what does smoking do to CYP450 enzymes?
- induces it
- so, smoking will increase clearance of some drugs
What are we talking about when we are asking about pharmacodynamic things?
-the drug target
Which CYP will do phase 1 for warfarin?
-CYP2C9
what is the antidote for warfarin?
-vitamin K
if someone has hemolytic anemia, what enzyme has a weird polymorphism?
-G6PD defect
