Metabolism and Biotransformation Lect 7 Flashcards
most pharmacologically active drugs have what qualities at physiological pH
- lipid soluble
- non-ionized
- strongly bound to plasma proteins and other tissues
what is the biotransofrmation of drugs
converts lipid-solube, non-ionized compounds to water-soluble, ionized metabolites
where are most drugs metoblized
liver
* some occurs in GI tract
what molecular weight classifications determines if a drug is excreted by the kidney or in bile
- MW < 350 is excreted by kidney
- MW > 350 is excreted in bile
give an example of a drug that must be metabolized to be active
codeine (prodrug) -> morphine (active metabolite)
Name a drug in which its metabolites are more active than the parent drug
Diazepam (active drug) -> Nordiazepam -> Oxazepam (both active metabolites)
Name a drug that is metabolized to toxic metabolites
acetaminophen (active drug) -> N-acetyl-p-benzoquinone imine (toxic metabolite)
What happens during phase I of biotransformation reactions
modification of molecule
- converts lipid-soluble, non-ionized compounds to more ionized, hydrophilic metabolites
- some metabolites are inactive and readily excreted
- other metabolites may undergo phase II conjugation
what happens during phase II biotransformation reactions
conjugation
- adds an ionized, charged particle (peptide, protein) to a phase I metabolite to form a more polar and hydrophilic conjugate
in some cases, phase II (conjugation) occurs before phase I (modification). Give an example
isoniazid
- acetylation (II) followed by hydrolysis (I)
- results in toxic metabolites
- high degree of genetic polymorphisms
what are the most common phase I reactions
oxidation
characteristics of phase I reactions
- not compound specific
- no specific enzymes metabolizing a particular drug
- enzymes attack functional groups or bonds of multiple drugs
- introduce or “unmask” chemical functional groups (OH, SH, NH2)
example of phase I reaction of a molcule that contains a benzene ring
- benzene ring can be hydroxylated (adding OH group)
- or an O-CH3 group can be de-methylated
what are cytochrome P450s (CPY450). What are their functions?
family of microsomal enzymes in the liver
- function: oxidation (formation of OH) of mulitple drugs; acts as a handle for phase II conjugation
function of CYP450 subtype CYP3A4
metabolizes >50% drugs
* drugs metabolized by 3A4 have high degree of drug interactions
function of CYP450 subtype CYP2D6
polymorphism impairs codeine metabolism
function of CYP450 subtype CYP2E1
metbolizes, and is induced by alcohol
all phase I microsomal enzymes (CYP450s) are inducible except which one
2D6
which is the only phase II enzyme which is microsomal and inducible
glucuronyl transferase
enzyme induction or inhibition can increase drug toxicity. In light of this, why do you not want to consume alcohol while taking acetaminophen?
ethanol induced CYP2E1 increasing acetaminophen metabolism and potential hepatotoxicity caused by metabolites
smoking and chargrilled foods induces what CYP enzyme
1A2
barbituates/phenobarbital, and St. John’s wort induce what CYP enzymes
- 2A6
- 2B6
- 2C8
- 2C9
- 2C18
- 3A4
ehtanol induces what CYP enzyme
2E1
grapefruit juice inhibits what CYP enzyme
3A4
Quinidine inhibits what CYP enzyme
2D6
function of monoamine oxidase (mitochondrial)
inactivates amines
warfarin is inactivated by a reduction reaction (adding H+) by what CYP enzyme
CYP2A6
hydrolytic reactions occur in plasma and in many tisues. Esterases and amidases are metabolized in this fashion by what enzyme
psuedocholinesterase
Esterases, amidases, alcohol dehydrogenase, and monoamine oxidase these enzymes are involved in CYP450 independent oxidative reactions. What does this mean
these enzymes are not inducible
where does the majority of phase II reactions (conjugation) occur. What are they mediated by
- liver
- glucuronidation and UGT (UDP glucuronyl transferase)
characteristics of end products of phase II reactions
- decreased lipid solubility
- polar and inactive
- have a large molecular weight
- readily eliminated
most common phase II conjugation
functional groups (OH, SH, NH2) conjugated with glucuronic acid
- glucuronic acid is transferred to the substrate, forming a bond via UGT (UDP glucuronyl transferase)
** biliruben and adrenal corticosteroids are conjugated by this system
sulfonamides, isoniazid, clonazepam, dapsone, and mescaline undergo what type of conjugation
acetylation
CYP2D6 has a large degree of polymorphisms: inhertied autosomal recessive trait. what is usually affected
- leads to poor metabolism of codeine to morphine
why does alcohol flush reaction occur
a condition found in Asian populations in which the face and/or body experiences flushes after consuming alcohol. Caused by the accumulation of acetaldehyde due to a polymorphism that encodes the enzyme, acetaldehyde dehydrogenase which metabolizes acetaldehyde, a toxic product of the alcohol metabolism
acetaminophen metablism can form toxic metabolites in chronic drinkers
- acetminophen is a GSH (glutathione)-conjugated metabolite
- increased production of free radicals may exhaust the supply and free radical molecules can then induce toxicity (oxidative stress)
describe “Freeing” of drugs in enterohepatic circulation
- The compounds secreted into the bile following liver metabolism are not always excreted but often go through the enterohepatic cycle and are reabsorbed
- Some glucuronides that are secreted into the bile are cleaved by glucuronidases in the small intestine, “freeing” the parent drug for reabsorption. (conjugate is removed and drug is freed)
what happens to half life of drugs that enter enterohepatic circulation
long half life
excretion of drugs is enhanced by what
- agents that bind drugs in the intestive (charcoal) increasing peristalsis
- antibiotics that eliminate GI bacteria
how does young age influence metabolism
- organ maturation is incomplete
- blood brain barrier is not fully developed
- liver function and renal excretion is not developed
how does being elderly influence metabolism
- decreased renal function occurs first
- decreased hepatic metabolism
- slower gastric emptying and decreased gastric secretion
how does liver cancer modify drug metabolism
patients have lower CYP450 enzymes resulting in slow metabolism of many drugs
drugs differ in the rate at which they are excreted by the kidney. How do penicillin and diazepam differ.
- PCN: cleared almost completely of a single transit through the kidney
- Diazepam: is cleared very slowly.
which is excreted more quickly: products of phase I and II metabolism or parent compound
products of phase I and II metabolism
what are the 3 basic processes that accoun for differences in renal excretion
- glomerular filtration
- active tubular secretion or reabsorption
- passive diffusion across tubular epithelium
