Drug Metabolism Flashcards
xenobiotics
foreign substances to biological systems, not natural and can reach toxic levels
cometabolism
enzymes that are present to metabolize endogenous agents also metabolize xenobiotics
ex. epinephrine is metabolized by monoamine oxidase (MAO) and exogenous amines such as tyramine are also metabolized by MAO
four characteristics that describe drug function
ADME - Absorption, Distribution, Metabolism, and Excretion
Phase I drug metabolism
place an alluring functional group on the drug to make it more polar and provide a reactive center for phase II reactions
Phase II drug metabolism
covalently conjugate the drug at the reactive center provided by Phase I reactions and also usually make drugs more polar
Phase I reactions
HOR - Hydrolysis, Oxidation, Reduction
Phase II reactions
SAGGMeth - Sulfation, Acetylation, Glucuronidation, Glutathione, Methylation
most common Phase I reaction
oxidation reactions are by far the most common
carried out by cytochrone P450 monooxygenases known as CYPs
CYP3A4 is the most common
most common Phase II reaction
glucuronidation
use and mechanism of action of midazolam
use - sedative/hypnotic used frequently as premedication prior to surgery or outpatient procedures
mechanism of action - a benzodiazepine, all benzodiazepines work on GABA(A) receptors, receptor channels open more frequently in the presence of benzodiazepine, increasing synaptic inhibition
generic benzodiazepine structure
7 membered ring with 2 nitrogens and 2 benzene groups attached
either _zolam or _zepam as suffixes
metabolism of medazolam
CYP34A hydroxylation in phase I followed by addition of glucuronide in phase II
oxidations
Phase I reaction, includes hydroxylations and oxidative dealkylations
reactions are carried out mostly by cytochrome P450 monooxygenases known as CYPs
what is the most prevalent CYP?
CYP3A
Where are CCYP enzymes found?
in liver and intestinal cells in the ER membrane
Describe the hydroxylation oxidation cycle.
key players are oxidase and reductase
two electrons and two protons are donated to form water and attach the OH group
therapeutic use and mechanism of action for propranolol
use - antihypertensive, anti-anginal, anti-arrhythmic, stage fright, etc.
mechanism of action - blocks beta1 adrenoreceptors (mediate increases in heart rate and cardiac contraction)
H2 histamine receptors
found in parietal cells, responds to histamine release from paracrine cells and promtoes HCl excretion
therapeutic use and mechanism of action for cimetidine (tagamet)
use - suppresses acid secrtion, wonder drug of the 1980s and early 1990s to treat ulcerative conditions, still frequently used for heartburn
mechanism of action - competitive inhibitor of histamine at H2 receptor
metabolism of cimetidine
undergoes S-Oxidation
inhibits a bunch of CYPs (CYP1A2, CYP2E1, CYP3A, CYP2D6, CYP2C) except for CYP2E1
therapeutic use and mechanism of action for diphenhydramine (Benadryl)
use - to treat mild allergic reactions
mechanism of action - competitive inhibitor of histamine at H1 receptors (H1 receptors are responsible for mild allergic reactions produced by histamine release from mast cells)
metabolism of diphenhydramine
N-oxidation
therapeutic use and mechanism of action for diazepam (valium)
use - to treat seizures, anxiety, muscle spasms and other disorders in which enhancing GABA(A) function would prove helpful
mechanism of action - increases the frequency of opening of GABA(A) receptors
metabolism of diazepam
N-dealkylation produces a very long acting metabolite
two active intermediates are nordazepam and oxazepam
O-dealkylation
codeine (weak agonist) to morphine (full agonist)
also hydrocodone to hydromorphone
done by CYP2D6
P450 independent oxidations
dehydrogenases such as alcohol dehydrogenase
amine oxidases such as monoamine oxidase
sulfate conjugation
occurs via sulfotransferases (13 isozymes)
cytosolic enzymes that require activated sulfate - 3’-phosphoadenosine-5’-phosphosulfate (PAPS)
therapeutic use and mechanism of action for acetaminophen
use - analgesic and antipyretic
mechanism of action - inhibits cyclooxygenase (COX)
metabolism of acetaminophen
sulfation
also inactivated by glucuronidation
actually prfers glucuronidation over sulfation
glucuronidation
occurs via glucuronyl transferases and is th emost common phase II reaction
the enzymes are in the smooth ER and require UDP (uridine 5’-diphosphate) glucuronic acid
lorazepam (ativan) metabolism
a benzodiazepine with no active intermeidates
undergoes clucoronide conjugation
all benzodiazepines are inactivated by glucuronide conjugation
glutathione
structurally a gamma-glutamyl-cysteinyl-glycine
site of reaction with electrophiles is the HS group
transferred to toxic electrophiles via glutathione-S transferase (GST)
glutathione S-transferase (GST)
approximately 20 human GSTs, extremely important to protect against toxic metabolites
GST is one of th emost common liver enzymes (comprises of 5% of the liver)
if impaired, increased risk of developing cancers such as CML
implicated in the development of resistance to chemotherapeutic agents
NAPQI
the resultant molecule when high doses of acetamenophen is processed by CYPE1 or CYP3A4
may be neutralized by GSH
possible antidote for acetominophen overdose
N-acetylcysteine
CYP2D6 polymorphisms
by far the most common polymorphisms
has a trimodal distribution with poor metabolizers, wild type, and ultraextensive metabolizers as peaks
substrates include beta blockers such as metoprolol, opioids, and tricyclic antidepressants
CYP2C19 polymorphisms
poor metabolizers in 15-25% of Asians
3-5% of caucasians
4-6% of African Americans
CYP2C19 substrates
diazepam and other zepam benzos
proton pump inhibitors such as omeprazole and other prazoles
NSAIDs
CYP2D6 poor metabolizers
inheritance of two mutant CYP2D6 alleles
no or very poor enzyme activity, impaired metabolism of substrates
high plasma drug leve, may need to lower the dose
caucasians 8-10% of population
African Americans 1-3%
Japanese/Chinese <1%
CYP2D6 ultraextensive metabolizers
duplication or amplification (up to 13 functional cpies)
excessive expression of enzyme, high metabolic capacity
Swedish 2% of population
Ethiopan and Saudi Arabian 30%
Why is diazepam (valium) metabolism slower in Asians as compared to Caucasians?
CYP2C19 - poor metabolizers
15-25% of Asians have mutant alleles
in poor metabolizers, the t1/2 can be >4x longer than normal
therapeutic use and mechanism of action for omeprazole
use - this drug and other prazoles are the proton pump inhibitors (PPIs), these are the current drugs of choice to treat disorders associated with excessive acid secretion
mechanism of action - irreversibly blocks the proton pump
N-acetyltransferase (NAT) polymorphisms
fast and slow acetylators, bimodal distribution
related to how much enzyme is synthesized, slow acetylators have less NAT
slow acetylator phenotype
in ~50% of blacks and whites
associated with higher incidence of drug induced autoimmune disease and some bladder cancers
toxic effects of isoniazid and other NAT substrates
GST and glutathione null genotypes
mu genotype (GST deficiency) expressed in 50% of caucasian population, linked to lung, colon, and bladder malignancies in humans
theta genotype (glutathione deficiency) as high as 60% in Chinese and Koreans, null activity associated with toxicity and adverse side effects with cancer chemotherapeutic drugs, cannot be cleared by glutathione conjugation
increased risk of CML
Why does CYP3A4 have such broad substrate specificity?
large active site and ligand promiscuity
others such as CYP1A2 have small active sites and ligand specificity
CYPE21 functions
processes ethanol at higher doses
creates toxic NAPQI from acetaminophen
ethanol and acetaminophen toxicity
induces CYP2E1 and helps create reactive toxic intermediate NAPQI
reduces GSH and prevents rescue from NAPQI
other factors that may affect the CYPs
environmental pollutants
picnics
herbal remedies
environmental pollutants and CYPs
induce CYP1A, responsibly for generating toxicity and carcinogenesis
pollutants include cigarette smoke which contain benzo(a)pyrines, polychlorinated biphenyls, and dioxin
other inducers of CYP1A (food products)
charbroiled foods and cruciferous vegetables
Gingko and CYPs
induces CYP2C19, 2C9, and 3A4
St. John’s Wort and CYPs
induces CYP3A4, 2C9, and 2E1
enhances the metabolism of oral contraceptives
echnacea
inhibits CYP1A2 and induces CYP3A4
What happens if two co-administered substrate drugs use the same CYP?
if residual levels of one drug remains at the active site, then it may inhibit the metabolism of the other drug
