What sort of enzymes are involved in Phase I and Phase II drug metabolism, respectively?
Phase I enzymes are oxydases (CYP450), reductases, and esterase-amidases (hydrolysis). Phase II enzymes are transferases.
What major property is modified in drug metabolism?
The ability of the drug to cross membranes. It becomes more water soluble, less lipid soluble, and larger through the metabolism process. Most importantly, this prevents it from crossing the membrane from the urine to the blood, or the metabolized drug may be excreted in bile to the gut.
Which phase is more affected by genetic polymorphisms? By saturation? Which can be more influenced by induction or inhibition?
Phase I is more affected by polymorphisms, Phase II is less so. Phase II is much more likely to become saturated, because it relies on less common substrates. Phase I is more inducible/inhibitable.
Five common sources shown to contain Phase I metabolism inducers
Cigarette/marijuana smoke, air pollutants, industrial chemicals, DDT, numerous drugs. Inducement of Phase I enzymes GENERALLY leads to increased clearance rate.
Which enzymes are most responsive to inducers, how do inducers work (generally), and how long do they take to show an effect?
CYP450 is the most inducible enzyme (most is known about it), but some Phase II enzymes (particularly UGT) are also inducible. Inducers generally cause increased synthesis of enzyme proteins (some decrease degradation of the same). Inducer effects are generally not seen for 48-72 hours after exposure.
Why does alcohol increase the risk of toxic side effects of acetaminophen?
Alcohol (particularly long term abuse of alcohol) induces the transcription of CYP2E1, which metabolizes acetaminophen to the hepatotoxic metabolite.
How long does it take to see the maximum effects of an inducer, and what impact does this have on drug dosage?
It takes 7-10 days for the maximum effects of an inducer to materialize. Because it takes 4-5 half-lives of a drug to attain steady state concentrations, there will be 4-5 half-lives of lag time between a change in dosage and correction of the steady state.
What is the equation that shows the rate in = rate out relationship?
MD/tau = Cp(ss) x CL
How long does it take for a metabolism inhibitor to show an effect? How long will it take to re-establish the steady state concentration of the target drug?
Only several hours, because they do not have to wait for protein synthesis to increase. Adjusting the drug dose to the new steady state will still take 4-5 half-lives.
How do diet, sex, and age influence drug metabolism?
Little is known about dietary effects in humans. Some evidence of differences between sexes. Some enzyme systems are not well developed at birth and have variable development throughout first year of life. 1/3 of elderly patients show a decrease in Phase I CYP450 with aging.
What are seven inducers of Phase I metabolism?
Phenobarbitol, Phenotoin, Carbamazepine, Rifampin, Ethanol, St. John's Wort, Tobacco smoke (not nicoteine).
What are seven inhibitors of Phase I metabolism enzymes?
Cimetidine, Erythromycin/Clarithromycin, Azole antifungals, Fluoxetine (other SSRIs), Grapefruit Juice, HIV Protease inhibitors, Omeprazole
What do P-glycoproteins do in general, and specifically in the GI tract, Liver-Kidney, and on the Blood-Brain Barrier?
Generally, they function to move drugs out of the cell. In the GI tract, they decrease the oral absorption of drugs. In the Liver-Kidney, they enhance biliary and renal excretion of drugs. In the Blood-Brain Barrier they limit the distribution of drugs to the brain, moving them out into the plasma.
What sort of effects are P-glycoproteins subject to?
Same as Phase I metabolizers. Genetic polymorphisms, inducers, and inhibitors all affect their actions. Inducers decrease therapeutic effectiveness of drugs transported by P-glycoproteins. Inhibitors decrease transport and may lead to drug toxicities.
What is excretion and how does it differ from elimination/metabolism? What are the routes of excretion?
Excretion is the elimination of unchanged drug. Hepatic metabolism is elimination of activity of the drug. Both cases eliminate activity of the drug. Drugs may be excreted through bile, urine, feces, sweat, breast milk, and expired air.
What factors govern glomerular filtration and excretion of drugs into the urine?
Protein binding - only free drug may be filtered, proteins are not filtered. Ionization - ionized drugs may be filtered, but may not cross back out of the urine via passive reabsorption. Movement of drug back out of the urine into the blood can be acheived through increased concentration gradient, lipid solubility, and unionized portion, and decreased size.
What are the typical GFR, active secretion, and actual urine production rates, and what effect does this have on drug excretion?
Normal GFR is ~120ml/min, active secretion is ~120-600ml/min, and urine creation is ~1ml/min. Therefor, the vast majority of the filter is reabsorbed, increasing the need to modify (metabolize) drugs before they can be excreted in quantity.
What effects does enterohepatic recirculation of a drug cause?
Enterohepatic recirculation keeps the drug out of the Cp, but increases duration of action. It is calculated into the doseing of the drug, thus is not a concern unless a second drug is administered which interupts enterohepatic recirculation, which would decrease the duration of the first drug.
What is an example of the interuption of enterohepatic recirculation?
Free estrogen in the gut is absorbed to the liver and converted to Estrogen-glucoronide and returned to the gut in bile. It is reconverted to free estrogen by bacteria in the gut and returns to the cycle. Antibiotics knock out the bacteria, and the metabolized estrogen is excreted.
What are considerations for nursing mothers and how much of a drug is typically excreted in the breast milk?
Weak base drugs will accumulate in the slightly acidic breast milk. They are usually present in concetrations less than 5% of the mother's plasma level, subject to first pass metabolism by the child, and only present a danger if the drugs are severely toxic.
What sort of drugs are excreted through respiration and what affects their rates?
Gases, alcohols, and volatile substances that move through simple diffussion. Drug is usually cleared without metabolism. The rate of highly soluble gases depends on the respiratory rate, and the rate for poorly soluble gases depends on blood flow.