What innate enzymes evolved to metabolize drugs?
Drugs are usually lipophilic molecules. They are metabolized by enzymes involved in cholesterol, steroid and bilirubin pathways
Why are drugs less absorbed in the stomach?
The drugs are basic and the stomach pH decreases the amount of drug pushed through the membrane.
What is it called when drugs are completely metabolized by the liver?
First pass metabolism. This happens when drugs are poorly absorbed by the GI tract. They have low bioavailability because of low absorption from the GI tract.
What is the usual route of metabolism of drugs in the liver?
Phase I enzymes metabolize the drug and metabolites are excreted in the urine.
What liver enzymes are typically rate limiting?
Phase I enzymes
What enzyme family is a family of mixed function oxidases (mono-oxygenases)?
Cytochrome P450 Family (CYP family)
What are the steps of CYP P450 in drug oxidation?
What is the role of NADPH cytochrome P450 reductase?
It reduces the oxidized drug complex to give a reduced product.
How did P450 get its name?
If you react the complex with CO, it absorbs under UV light at 450.
Where do CYP reactions take place?
Lipid bilayer of the endoplasmic reticulum
What is the center key element of P450?
Fe centered in a heme group
Why can the liver have such high metabolism by P450?
It has lots of endoplasmic reticulum
How does CYP P450 change drugs?
It changes lipophilic molecules to more hydrophilic molecules that are easier to excrete.
Where are GI P450s found?
The small intestine wall
40% of drugs metabolized by phase I are metabolized by these two enzymes.
CYP3A4 and CYP3A5
What major drugs are metabolized by CYP1A2?
Tylenol, caffeine, theophylline and warfarin
What major drugs are metabolized by CYP2A6?
Zidovudine and warfarin if CYP1A2 is not ready to metabolize it.
What major drugs are metabolized by CYP2C9?
Phenytoin, S-warfarin (active enantiomer), hexobarbital and ibuprofen
What major drugs are metabolized by CYP2C19
Diazepam, omeprazole and propranolol
What major drugs are metabolized by CYP2D6?
Fluoxetine and codeine. This enzyme converts inactive drugs to active drugs.
What major drugs are metabolized by CYP2E1?
Tylenol. This enzyme is induced by ethanol.
What genetic variation in metabolism enzyme might a person who is resistant to codeine have?
What major drugs are metabolized by CYP3A4?
Steroids, Ca channel blockers, benzodiazepines, amiodarone, and erythromycin
What other phase I enzymes catalyze oxidation?
Flavin monoxygenases, alcohol dehydrogenases and amine oxidases
What other phase I enzymes catalyze hydrolysis?
Esterases and amidases
What other phase I enzymes catalyze reduction?
Compounds that reduce Nitro and Azo compounds
Why are phase II reactions called synthetic reactions?
Enzymes add a polar or charged hydrophilic group to the drug.
What major reactions are carried out by phase II enzymes?
Glucuronidation, sulfation, acetylation, glutathione conjugation, glycine conjugation and methylation
What are the major enzymes in phase II reactions?
UDP glucuronide transferases
What conjugation reaction plays a role in immune reactions?
Acetylation of histamine allows for its release.
What is a consequence of decreased NAT2 enzyme?
Increase in toxic metabolite accumulation
What drugs are activated by synthetic reactions (glucuronidation)?
Morphine on the 6' site. If glucuronide is added on the 3 position it is inactivated. Minoxidil is converted to minoxidil sulfate.
What is a major factor of CYP enzyme rate limitation?
NADPH. When enzymes are saturated, elimination becomes zero order and you put yourself at risk for toxicity because the liver is not taking drugs out of the blood as quickly.
Why do people get drunk quicker after 4-5 beers?
They have saturated alcohol dehydrogenase and elimination decreases to zero order and blood alcohol is eliminated more slowly.
What happens as a result of enzyme induction by a drug?
More enzymes are produced and can turn over more drug. However, this can increase toxicity or reduce drug efficacy because it is metabolized faster.
How do drugs increase the rate of production of the enzyme that metabolizes them?
What receptors do drugs act on to cause enzyme induction?
RXR, PXR, CAR and AHR receptors. Binding leads to overproduction of CYP P450 enzymes.
Why shouldn't you drink when taking tylenol?
Alcohol induces CYP2E1 and increases enzyme levels. Tylenol is metabolized by this enzyme and a very toxic metabolite is produced.
How are CYP P450s commonly inhibited?
Inactivation of or competition with heme group or competition for NADPH.
Major CYP Inhibitors
Macrolide antibiotics (erythromycin but not azithromycin), antifungals (ketoconozole), ritonavir, fluoxetine, nefazodone and cimetidine
When should your ears perk up about considering drug interactions?
Low therapeutic index, high first pass metabolism, high plasma protein binding (could be released after addition of another drug), single route of elimination and polypharmacy.
Drugs with high indexes of suspicion.
Anti-seizure, protease inhibitors, statins, warfarin,digoxin
How does Tb treatment decrease effectiveness of ritanovir?
It induces CYP3A4. CYP3A4 metabolizes ritanovir out of the system. Additionally, ritanovir inhibits CP3A4 and results in rifampin toxicity.
What other food can you eat to increase efficacy of statins?
Grapefruit juice because it has CYP3A4 inhibitors. Statins are metabolized rapidly in the liver and gut by CYP3A4. Grapefruit juice increases bioavailability.