Drug Metabolism Flashcards
Most of the Phase 1 reactions are part of
cytochrome p450 system
most of the phase 1 reactions are..
oxidations (OH, SH, NH2, COH, COOH) in addition there are hydrolysis reactions, reduction, dehalogentation, dehydrogenation, and dealkylation
phase 1 reactions’ role
to prepare lipophilic drugs for the addition of functional groups or add them
it doesnt necessarily convert inactive to active; it can make something an active metabolite, inactive metabolite, or convert pro-drug into drug
most of the phase 2 reactions are..
carried out by transferases
phase 2 tends to be _____, while phase 1 is _______
conjugation; oxidation
most common conjugation =
glucuronidation
glucuronidation is often followed by:
sulfation
other conjugations carried out in phase 2:
of amino acids; acetylation and methylation
all of phase 2 focuses on using the reactions to do what
get the drug out of the body
2 main goals of phase 2
enhance solubility and to detoxify (to reduce the toxic effects of the parent or metabolized drug and usually it creates non-toxic metabolites
the Cytochrome P450 isoenzyme is
responsible for 75% of drug metabolism and is predominately responsible for phase 1 of drug metabolism
cytochrome P450 transfers e-
between oxidized (fe3+) and reduced (fe2+) forms of iron
how many CYP genes in nature vs. in humans
6,000 vs. 57
Classification system CYP2D6
2 = family d = subfamily 6 = isoenzyme
Humans have ____ CYP families and ______ CYP enzymes in drug metabolism
4 families and 15 enzymes
90% of drug metabolism is carried out by:
1A2, 2C9, 2C19, 2D6, 2E1 (alcohol) , and 3A4 (HIV drug that we learned about)
location of cyp450
smooth ER of liver and kidney and in enterocytes (contributing to first pass metabolism)
cyp450 activity
substrates- drugs, chemicals or hormones that undergo biotransformation by cyp450 (acetaminophen)
inducers- that enhance the enzyme activity and increase metabolism of substrate (ciproflaxin)
inhibitors- decrease metabolism of substrate (phenytoin)
substrate activity depends on
km, the concentration of substrate required to reach 50% vmax
small km
means you only need a small amount of substrate to be very active
large km
means you need alot of substrate to reach vmax
example of the substrate activity dependence on km
at low ethanol conc. the enzyme with the low km (ADH) predominates metabolism. at high ethanol concentrations CYP2E1 takes over, which has a high km
When you hear about people that can metabolize alcohol faster than others, its because of conformational changes. So if you constantly expose your body to alcohol, you actually metabolize it better than those who don’t drink it on a regular basis
Substrate selectivity
determined by molecular, physiologic, biochemical, and other factors
stereoisomers
acidic/basic
lipophilicity
Example of substrate selectivity
S-warfarin and R-warfarin do not have the same CYP metabolism (S-warfain accounts for 70% of activity and is metabolized by 2C9) (R-warfain is metabolized by 3A4, 1A1 and 1A2)
