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57 terms

Drug Metabolism - MedChem

drugs and other substances that are foreign to the body
where is metabolism of xenobiotics?
in the hepatocytes of the liver
extrahepatic drug metabolism
gut (!), lung, kidney, skin
net result of drug metabolism
water soluble product (for excretion in water or bile)
4 effects of metabolism on drug action
1. inactivation or attenuation of activity 2. maintenance of activity 3. enhancement of activity 4. bioactivation (conversion of inactive drug to an active metabolite)
-OCH3 to -OH
-NCH3 to -NH
sulfate conjugation
-OH to _OSO3
influences on rate of drug metabolism
age (decreased in elderly), gender (sex hormones), diet and nutritional status, disease states (particularly liver disease and including stress), exposure to environmental chemicals, co-administerd drug products (enzyme competition can lead to higher drug levels; enzyme induction leads to lower drug levels), genetic differences in met rate (pharmacogenetics)
oral drugs gain access to peripheral venous circulation via
hepatic portal system (first pass metabolism)
prehepatic metabolism
in mucosa of gut which is rich in oxidizing enzymes and trasferase enzymes
CYP inhibition is dependant on
dose; some (isotopes) are affected by low and others by high doses
Phase I reactions result in lipophilic or hydrophilic metabolites?
hydrophilic (polar)
3 general classes of phase I reactions
oxidations, reductions, hydrolyses
function of cytochrome p450
insert a single oxygen atom into their substrates to increase the oxidation state of the metabolites compared to the parent drug (ie replace -H with -OH)
requirements for CYP450 metabolism
heme protein (resting state when bound to Fe3+, oxidized form, and in active state when bound to Fe2+, reduced form), NADPH (activator), phosphatidylcholine (facilitates electron transfer from NADPH protein to CYP450 heme protein), O2 (provides O atom donated to substrate to form oxidized metabolism)
most common CYP450 isoforms
3A4, 2D6 (then 25% from 2C9 and 2C19)
grapefruit juice, peel, and sections are inhibitors of
CYP3A4 (promote higher-than-expected level of drugs in body because enzyme is inhibited)
what does 2D6 metabolize?
lipophilic amines (cationic conjugate acids of amine-containing stubstrates bind ion-ion bonds with the enzyme's anionic ASP residue)
what genetic variations are expressed through 2D6?
50% chinese-amer, 34% black, 20% Caucasian are poor 2D6 metabolizers and could have drug toxicity; 20-30% of Saudi Ar and Ethiopians are ultrafast or extensive metabolizers
CYP 2C9 and 2C19 are found
in liver and gut
biotransforms 19% of xenobiotics (30% of Northern Europeans have this allele)
less extensive, but biotransforms common therapeutic agens s a PPI's. 30% of Asians are poor metabolizers
CYP 2C8 and 2C18 are found
activates environmental carcinogens and metabolizes 8% of clinically relevant drugs. in stomach, liver, and intestine. can be induced by cigarette smoke; important factor in gastric cancer. higher in men than women
Other oxidizing enzymes found (beside CYP) in cytoplasm and mitochondria
cytoplasm (alcohol dehydrogenase, aldehyde dehydrogenase, aldehyde oxidase); mitochondria (monoamine oxygenase or MAO)
hydroxylation (enzyme, product)
CYP450; -CH to OH
phenyl ring hydroxylation
at p-position unless blocked by substituent; followed by phase 2 conjugation with glucuronic acid or sulfate
indole ring hydroxylation
at C5 unless blocked by substituent
what does blocking degradative metabolism at vulnerable positions with a stable functional group do?
strategy in drug design to increase duration of action (use a halogen for example)
cycloalkyl hydroxylation
CH2 groups immediately adjacent to phenyl ring (benzylic C); if there are two benzylic C's, only one will be hydroxylated but both have an equal chance of being attacked
replaces a small alkyl chain (smaller than propyl) on a nitrogen atom with a hydrogen atom
What happens to alkyl side chains larger than propyl?
omega or omega-1 hydroxylation (too large for dealkylation)
What does CYP450 need in order to N-dealkylate?
an alpha-hydrogen (H on alpha C; alpha-C is next to N on side chain) to oxidize an OH group for unstable carbinolamine intermediate
What happens to the unstable carbinolamine intermediate?
decomposes to the N-dealkylated metabolite
What gets oxidized in N-dealkylation?
side chain (not metabolite) is oxidized and released as formaldehyde
What is left at the end of an O-dealkylation?
phenolic metabolite (loss of alkyl group, replaced with H) and formaldehyde
Which amines can undergo deamination?
primary amines (secondary and tertiary must first undergo dealkylation to produce free NH2 group)
byproduct of N-dealkylation or O-dealkylation?
where is deamination and dealkylation cut?
deamination is on drug side of N, dealkylation is on side chain side.
what is the product of deamination startng with 2 alpha-H's?
aldehyde, then carboxylic acid
What enzyme conducts deamination?
both CYP and MAO. MAO requires 2 alpha H's!!
What metabolite product comes from MAO deamination?
aldehyde (because it requires 2 alpha H's!)
What type of metabolite will be produced if there is only one alpha-H on drug side of N?
ketone (R-CO-R) (and this can only be processed by CYP450!)
When does N-oxidation occur and what is it catalyzed by?
1. Nitrogen atoms found in rings can oxidize to N-oxides (tertiary amines and amides) or hydroxylamines (primary and secondary amides) 2. N-oxidation on straight chain amines that cannot deaminate due to lack of alpha-hydrogens; via CYP450 or FMO
When does S-oxidation occur and what is it catalyzed by?
R-S-R are oxidized via FMO to sulfoxide (add one O) or sulfone (add two O's) metabolites
What can reduce ketones to alcohols?
ketone reductase
What can reduce both ketones and aldehydes back to alcohols?
alcohol dehydrogenase (which can also take alcohols to aldehydes). This doesn't happen often because most aldehydes go to CA's via aldehyde oxidase or dehydrogenase
What does hydrolyze mean?
split or cleave (lyse) and add water (hydro)
What functional groups are vulnerable to hydrolysis?
esters (R-C=O-OR) and amides (R-C=O-NR2)
What is cholinesterase?
membrane-bound enzyme found exclusively on cholinergic neurons, and regulates the concentration of the neurotransmitter acetylcholine.
What is the product of ester hydrolysis and what enzyme is involved?
Carboxylic acid and alcohol or phenol; carboxylesterases (esterase)
What are the 2 characteristics that influence the rate of ester hydrolysis?
#1 facilitated by strong partial positive character on carbonyl carbon (most critical) #2 inhibited by steric hindrance (more critical than electronic issues only if substituent is large)
What gives a strong partial positive character to carbonyl carbon?
resonance delocalization (ring attached, but not bulky is fastest!) and negative induction (CNOX)
What can hydrolyze amides?
esterase or amidase. Amides are much more stable to hydrolysis by esterase than are esters
How are drugs containing an amide linkage often excreted?
with the amide group intact
What is the product of amide hydrolysis?
CA and an amine