lecture 5 part 1 Flashcards
name the things that can happen to a drug after it is metabolized
active drug can become:
-a less toxic metabolite
-toxic metabolite
-inactive
an inactive drug (prodrug) can get activated after metabolism
metabolism consists of …
anabolism + catabolism
anabolism = synthesize
catabolism = destroy
biotransformation mostly has GOOD effects.
give 4 exceptions
-drug-drug interactions
-metabolic activation of toxic and carcinogenic derivatives
-variations in humans to metabolize drugs
-use of animal models is limited bc different species express different metabolic enzymes
true or false
some rectal drugs get absorbed and some dont
true
enema does not
a pediatric drug probably would
what kind of molecules are easily eliminated through the renal route
polar, hydrophilic molecules
true or false
very few drugs are polar and ionized
TRUE
most are lipophilic and unionized in physiological conditions
many ____ compounds are bound to plasma proteins and thus cannot……..
lipophilic
cannot pass glomerular filtration
_______ is an obstacle to drug excretion
LIPOPHILICITY
TRUE OR FALSE
metabolism always produces drugs that are more hydrophilic and less toxic
FALSE
sometimes they can retain their biological activity and even be toxic
the renal excretion of unchanged drug contributes _______ to elimination.
explain
only slightly, because the unchanged, lipophilic drug can be easily reabsorbed back into the body through the renal tubular membranes
true or false
metabolism can turn an active drug into a different active drug
true
drug biotransformation mechanisms are described as….
either phase 1 or phase 2
explain (in general) what happens in phase 1 metabolism
the parent drug is altered by introducing or exposing a functional group
name 3 functional groups that can be introduced/exposed in phase 1 metabolism
OH
SH
NH2
inactive prodrugs can be metabolized into biologically active metabolites
is this done through phase 1 or phase 2
phase 1
classify types of prodrugs
they can either have an intracellular or extracellular site of conversion
intracellular - subtypes A and B
A - location of conversion is the therapeutic TARGET tissues/cells
B - location of conversion is METABOLIC tissues such as liver, GI mucosal cell, lung, etc
extracellular - subtypes A, B, C
A - location of conversion is GI fluids
B - location of conversion is systemic circulation and other extracellular fluid compartments
C - location of conversion is THERAPEUTIC target tissues/cells
explain the potential fates of phase 1 reaction products
-directly excreted in the urine
or
-react with endogenous compounds to form more water soluble conjugates (AKA go through phase 2)
explain the characteristics of phase 2 metabolic reactions
the drug participates in CONJUGATION reactions that forms a COVALENT BOND between the parent functional group and potential endogenous substances
glucuronate
sulfate
glutathione
amino acids
acetate
name the enzyme involved in adding glucuronate in phase 2
UDP glucuronosyltransferase
name the enzyme involved in adding sulfate in phase 2
sulfotransferase
name the enzyme involved in adding glutathione in phase 2
glutathione-s-transferase
name an enzyme involved in adding amino acids in phase 2
acyl-coa glycinetransferase
name the enzyme involved in adding acetate in phase 2
n-acetyltransferase
explain the conjugates of phase 2 and any exceptions
highly polar
rapidly excreted in the urine
GENERALLY inactive
exception - the glucuronide metabolite of morphine is A MORE POTENT ANALGESIC than the parent compound
true or false
all phase 2 metabolites are inactive
FALSE
most, but an exception is morphine
glucuronide metabolite of morphine is a more potent analgesic than the parent
explain what happens to HIGH MOLECULAR WEIGHT conjugates
they are excreted in the bile (feces)
may go through enterohepatic circulation
-the conjugate bond may be cleaved my the intestinal flora and the parent drug may be released BACK into systemic circulation
this leads to delayed elimination of the parent drug and prolongation of drug effect
name some high molecular weight drugs that may go through enterohepatic circulation
morphine and tetracyclines
what is the principal organ for biotransformation?
name 5 others
LIVER
GI tract
lungs
skin
kidney
brain
_____ is responsible for 1st pass effects
metabolism
give 2 examples of “first pass” when a drug is given orally
- drug is administered orally and absorbed intact through the small intestine
- the drug is transported to the liver portal system
—extensive metabolism here (1st pass)
- a drig is administered orally and is absorbed intact through the small intestine
-the drug may undergo extensove INTESTINAL metabolism which will contribute to the overall 1st pass effect
give 4 examples of drugs that….
are administered orally, absorbed intact through SI, and then are carried to the liver portal system where they undergo 1st pass
meperidine**
morphine
isoproterenol
pentazocine
give 4 examples of drugs that….
are administered orally and absorbed intact through the SI, then undergo extensive INTESTINAL METABOLISM that contributes to overall 1st pass
cyclosporine
clonazepam
midazolam (50%)
chlorpromazine
give an example of a drug that is UNSTABLE IN GASTRIC ACID
what does this contribute to
penicillin
contributes to overall 1st pass effects
give an example of a drug that is metabolized by digestive enzymes and why.
what does this contribute to
insulin - that’s why given SUBQ.
bc it is a peptide it is metabolized by digestive enzymes
contributes to overall 1st pass effetcs
what kind of drugs are metabolized by intestinal wall enzymes
sympathomimetic and catecholamines
which route of administration has the highest bioavailability
IV
why is the bioavailability of oral drugs so limited
bc of 1st pass effects
true or false
the intestinal flora may metabolize drugs and this could contribute to overall 1st pass effects
true
the bioavailability of oral drugs is so limited that…….
sometimes alternative routes of administration must be used (ie: lidocaine)
name the cytochrome p450 dependent oxidation reactions
aromatic hydroxylations
aliphatic hydroxylations
epoxidation
O-dealkylation (N,O,S)
N-oxidation
S-oxidation
Deamination
desulfurization
dechlorination
what are the cytochrome p450 INDENDENT oxidations
flavin monoxygenase (Ziegler’s enzyme)
name 3 kinds of reductions
azo reductions
nitro reductions
carbonyl reductions
name 2 structures that undergo phase 1 hydrolysis
esters
amides
what does FMO stand for
Flavin containing monooxygenases
-superfamily of phase 1 in drug metabolism. CYTOCHROME P450 INDEPENDENT
Where are FMOs expressed in high levels
in the liver, bound to the ER
how many families of FMO are there? which is most abundant
6 families
FMO3 is MOST ABUNDANT in human liver
what happens if someone has a genetic deficiency of FMO
fish odor syndrome
lack of TMAO (tri methylamine N-oxide) metabolism to TMA (tri methyl amine) leads to its accumulation in the body
what does TMAO stand for and what is it
trimethyl amine N-oxide
it’s supposed to get metabolized by FMO system (cytp450 independent) to TMA (trimethylamine), but when a person is genetically deficient in FMO, they get FISH ODOR SYNDROME because TMAO builds up in the body
where is TMAO found in high concentrations
in murine animals (rodents
-up to 15% of their body weight!
TRUE OR FALSE
CYPs are not induced or inhibited by any clinically used drugs, while FMO is.
FALSE
CYPs ARE induced/inhibited by clinically used drufs
FMO is NOT
name some drugs that FMO3 metabolizes
nicotine
H2 receptor antagonists (cimetidine and ranitidine)
antpsychotics
antiemetics
name a hydrolytic enzyme
the epoxide hydrolases —
sEH (soluble epoxide hydrolases) in the cytosol
mEH (microsomal epoxide hydrolases) in the ER
what produces epoxide hydrolases ? (sEH and mEH)
CYPs
what are epoxides
highly reactive electrophiles that bind to nucleophiles found in protein, RNA, and DNA (dangerous!)
what is the function of epoxide hydrolases
the deactivate potentially toxic metabolites that are generated by CYPs (like epoxides)
give a specific example of epoxide hydrolases in action
carbamazepine (prodrug - antiepileptic)
gets metabolizes to carbamazepine 10,11-EPOXIDE by a CYP.
this gets HYDROLYZED to a Dihydrodiol by mEH.
Give the “rhyme” for metabolism
active to inactive
active to reactive (toxic)
active to active
inactive to active
LIVER MICROSOMAL SYSTEM
give an example of when an active drug is metabolized to an inactive, polar metabolite
phenobarbital is converted to barbituric acid by CYP2c19 isoform.
barbituric acid is INACTIVE and further undergoes phase 2 glucuronidation or sulfation (sulfuric acid) and is excreted in the urine
phenobarbital has the potential to induce what enzymes
CYP2CP and CYP3A4
give a specific example of an inactive drug getting metabolized to an active metabolite
this is the case for prodrugs
-purine and pyrimidine chemotherapy drugs
-terfenadine -> fexofenadine (inadvertant)
-L-dopa –> dopamine
give a specific example of an active drug getting metabolized to a reactive/toxic metabolite
acetaminophen (when glucuronidation and sulfation are saturated)
becomes NAPQI
give a specific example of an active drug getting metabolized to a different active drug
digitoxin metabolized to digoxin
-has same pharmacological activity
the metabolite is still active and working
more than ______ individual CYPs have been identified in humans.
what are the categories based on?
more than 50
categories based on protein sequence homology
true or false
CYPs cannot metabolize a single compound at different positions on the molecule
FALSE - they can
most of the DRUG-METABOLIZING enzymes are in what CYP families?
CYP 1,2,3
What is the range of MW of CYPs
45-60kDa
____ is VERY COMMON to the metabolism of many drugs.
explain
CYP3A4
its presence in the GI tract is responsible for the poor oral availability of many drugs
what is responsible for the poor oral availabiltiy of many drugs
CYP3A4 presence in the GI TRAT
true or false
CYPs have redundant and broad substrate specificiy
true
frequently, 2 or more enzymes can catalyze the same type of ocidation
how many putative functional genes are in the mouse/human?
what about pseudogenes
human:
-57 putative functional genes
-58 pseduogenes
mouse:
-102 putative functional genes
-88 pseudogenes
explain the nomenclature of CYPs
CYP3A4
3 = family (arabic number)
A = subfamily
4=additional number when more than 1 subfamily is identified
if 4 was in ITALICS – it would indicate the gene
if NOT in italics = enzyme
give the formula for the CYP reactions
NADPH + H+ + drug -> NADP+ + H20 + oxidized drug
what is the cofactor in the CYP reactions
NADPH
what is the origin of the enzyme family name of CYP
carbon monoxide binds to the reduced Fe(II) heme at 450nm
___________ is the major catalyst of drugs and endogenous compound oxidations in the liver, kidney, GI, skin, and lungs
CYP monooxygenase enzyme family
name 5 things that oxidation reactions require
CYP heme protein
reductase
NADPH
phosphatidylcholine
molecular Oxygen
where are CYPs? what are they with close association with and in what ratio?
in smooth ER
Close association with NADPH-CYP reductase in 10:1 ratio
NADPH cytochrome P450 reductase serves as…….
the source of electrons for the oxidative reaction cycle
what is another name for the heme portion of CYP
Iron-protoprophyrin IX
go back to CYP cycle
go back
majority of drugs are metabolized by what CYP isoforms
CYP3A4
CYP2C9
CYP2D6
ALSO…..
CYP2C19
CYP1A2
CYP2A6
TRUE OR FALSE
in addition to metabolizing exogenous substances like drugs, CYP isoforms also metabolize many endogenous substances including prostaglandins, lipids, fatty acids, and steroid hormones
TRUE
ethanol induces what CYP isoform?*****
CYP2E1
isosafrole induces what CYP isoform
CYP1A2
what is “induction mechanism 2” of CYP
p450 enzymes may be induced by substrate stabilization (decreased degradation)
such is the case for ethanol induces CYP2E1
troleandomycin and clotrimazole induce what cytochrome isoform
CYP3A enzymes
true or false
some drugs inhibit CYTp450s
true
give examples of drugs that are COMPETITIVE INHIBITORS of CYT P450 enzymes***
they bind to the cytochrome component (thus competitive inhibitors)
cimetidine – CYP3A4 and CYP2D6 (anti ulcer H2 receptor blocker)
ketoconazole – CYP3A4 and CYP2D6 (antifungal)
besides cimetadine and ketokonazole, give another example of a drug that is a CYP inhibitor and explain how it works
chloramphenicol (antibiotic) is metabolized (by CYP2B1) TO AN ALKYLATING METABOLITE THAT INACTIVATES THAT CYP ISOFORM
If you take a drug that is a substrate for CYP3A4 and a drug that is an inducer of CYP3A4, what will happen?
what is you take an inhibitor?
the drug will be metabolized extremely quickly
with inhibitor – drug will not be metabolized nearly as fast and will remain the body longer - potential toxicity
5-10% of caucasians are poor metabolizers of…….
substrates for CYP2D6
explain the poor metabolizers of CYP2C19 drugs
about 20% of asian populations are poor metabolizers of drugs that are substrates for CYP2C19
but only about 4% in caucasian populations
true or false
water conjugation is a type of phase 2 biotransformation
TRUE – enzyme is epoxide hydrolases in cytosol or microsomes (mEH or sEH)
