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131 Cards in this Set
- Front
- Back
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Most drugs are taken into the body are
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lipid soluble
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What does metabolism do to drugs
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converts to water soluble
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What is the definiation of drug metabolism
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enzymatic conversion of drugs to metabolites
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What are metabolites
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different chemical entites that usually exhibit higher water solubiliy than the substrate and are more rapidly excreted from the body
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Most metabolites are...
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inactive---but some have pharacoligcal activity and some are toxic
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What does drug elimination =
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excretion+metabolism
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What is Phase I of drug metabolism
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addition of a new or alteration of an existing functional group
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What is Phase II of drug metabolism
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syntheis of a drug conjugate (linking the drug to something else ALREADY in the cell)
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What is the most importatn Phase I enzyme that performs oxidations
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CYP 450
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What type of protine is CPY 450
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heme protien
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Where is the heme protein mainly located, and where else
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in the liver...but located in many other tissue
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What is the prothetic(non-protein part) of the P450
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heme group
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Where is the prosthetic group of the enzyme sitting
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in a pocket of hydrophobic amino acids (the active site)
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How the the heme held into the protein?
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through a side-chain sulfur atom of a cysteine residue, and this thiol group is ionized to a thiolate
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What is bonded to the heme iron
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thiolate--make P450 unique
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What is 1st part of reaction cycle of P450
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the substrate enters the active site of the heme and knocks off the water molecule that was bound to Fe
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What happens after substrate enters and knocks off the water molecule
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the heme is reduced by cyt P450 reductase
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Where is cyt P450 reductase located
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another enzyme located close to P450 in the cell
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What does cyt P450 reductase do
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transfer one elctron from NADPH to the P450 heme IRON to convert Fe+3 to Fe+2
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Fe+3 is feric form---what is Fe+2
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ferrous form
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What happens when iron is in the Ferrous Fe+2 form
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the heme iron can bind molecular oxygen O2
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What happens after molecular O2 binds
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The P450 oxygen complex is reduced a second time as Cyt P450 reducdase donating one more electron
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What happens as soon as the second electron is received by the complex
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the 0-0 complex is rapidly cleaved to form the REACTIVE heme oxo species FeO and water
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What does the reactive heme oxo species FeO do and form
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(ACTIVE FORM OF ENZYME)can now oxidize the substrate to form a metabolite and returns the enzyme to its resting state
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What is a aliphatic hydroxylation
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NON aromatic compound
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Types of Aliphatic hydroxylation
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1. Side chain
2. Apliphatic rings (non-aromatic) 3. benzylic and allylic positions |
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How are all saturated aliphatic positions oxidized by FeO, and what does it form
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by abstration of a hydrogen atom (transfer of H to FeO) to form a carbon free radical and FeOH
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Where is the hydrogen removed most frequently
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the w-1--the omega -1 carbon
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Where is the omega carbon
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the last carbon at the end of the chain
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What happens after formation of FeOH (iron bond hydroxyl radical)
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radical recombination between this and the carbon radical
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What happens after radical recombination
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is the formation of the hydroxlated product
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What is heteroatom dealkylation the same as
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same as aliphatic hydroxlation
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What is different about heteroatom dealkylation
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the hydroxylated product is unstable and spontaneously decomposes
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What does the heteroatom spontaneously decompose to
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to the dealkylated product and an aldehyde or ketone
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Dealkylation of secondaary and tertiary amines leads to
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primary and secondary amines
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Usually dealkylation occur with what type of alkyl group
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smaller alkyl group meth >eth >pro
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Where does satruated apilphatic rings undergo hydroxylation
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at the least hindered part
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What happens to side chain hydroxylation attched to aromatic rings
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occurs preferably on teh benzylic methylene group--and then other side chains
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What is mechanism of O-dealkylation of ethers
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same as N-alkylation--forms an unstable intermediate, it is a REMOVAL of an alky (methyl) group
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What is product of O-dealkylation of ETHER
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an alcohol and a carbonyl
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What is mechanism of S-dealkyation of Sulfides
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same as heteroatom dealkyation--formation of unstable intermediate--products are SH and carbonyl
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What is the result of expoidation
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alkene or alkyne forms an expoxide
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What does EH (enzyme epoxide hydrolase do to epoxides
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converts to DIOLS
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Is aromatic hydroxylation like alkene and alkyne hydroxylation
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NO--it doesnt form an expoxide--it forms an unstable intermated ARENE oxide
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What happens after the formation of unstable arene oxide
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followed IMMEDIATELY by a non-enzymatic re-aromatization
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B/c the arene oxide is not stable what does it ultimately form
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it forms phenol
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For monosubsituted benze compounds, what region is usually hydroxalated
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the PARA position, then ortho
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When there is more than one aromatic ring, how many is hydroxlated
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only one
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Does aromatic hydroxlation occur in a ring with 2 or 3 substituents
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NO---only occurs farest from substituents--it should be at least 2 position from any substituent
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Can arene oxide adn epoxide sometimes be toxic and why
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YES, they are electrophiles and other (nucleophiles) can link to and be potentially toxic
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What is heteroatom oxidation or N oxides
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addition of an oxygen to the amine
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What enzymes are involved in formation fo N-oxides
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p450 and FMO
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What happens to oxidation to Sulfides
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form sulfoxides or carbonyl attach to an S
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Does cytochrome P450 exists in multiple form
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YES
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For apliphatic hydroxylation of side chains what are 2 KEY POINTS
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1. W-1 position is prefered
2. Longer side chains are prefered over short onces when BOTH appear |
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For apliphatic hydroxylation of SATURATED aliphatic rings what is key point and what about position next to carbamate
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hydroxylation occurs at saturating ring carbon FAR from existing subsitutents
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What is key point for benzylic and allylic poistions
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1. Benzylic most likely
2. Allyic 2nd liekyl |
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Expoxiation occurs preferentialyl at double bonds remote from existing substiutents and most likely occur in RINGS with how many substituents
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ONE or TWO ortho SUBsituents
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What are key points for N-dealkylation, O, and S dealkyation
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attack is preferred at meth, ehth and pro
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What are tertirary amines converted to under heteroatom oxidation
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N-oxides
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What are sulfide converted to
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sulfoxides,
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What are sulfoxides converted to
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sulfones---S with TWO carbonyls
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What are other hydrolyic enzymes that are important in Phase I metabolism
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1. Esterases
2. Amidases 3. Epoxides Hydrolases |
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Where are esterases located
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in both LIVER and blood
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What are the products of metabolisms of esterases
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carboxylic acid and the alcohol (side product)
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Where are amidases located
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only in LIVER
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Whata re the products of metabolism of amidases
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carboxcylic acids and amine
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What are enzymes responsible for dehydrogenases/reductases
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1. Alcohol dehydrogenase (ADH)
2. Aldehyde dehydrogenase (ALDH) |
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Where dehydrogenases reaction is reversible, and what does it do
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ONLY alcohol dehydrongenase, converts alcohol to carbonyls and carbonyls to alcohols
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What type of alcohols does alcohol dehydrogenase prefer
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PRIMARY alcohols and converts to an aldehyde
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Some secondary alcohol are excreted or converted by alcohol dehydrogenase to
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a KETONE
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Does alcohol dehydrogenase do to tertiary alcohols
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NOTHING
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What else does alcohol dehydrogenase do besides converting primary and secondary alcohols to aldehydes and ketones, using what
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Also functions as a reductase--also reduces an ALDEHYDE or ketone to an ALCOHOL --using NADH
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What does aldehyde dehydrogenase do (ALDH)
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converts an aldehyde to a carboxcylic acid
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What does aldehyde dehydrogenase do
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converts an aldehyde to a carboxcylic
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What are step to go from a primary alcohol to an carboxcylic
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alcohol b/c aldehydte by ADH, and they aldehyde is converted to a carboxcylic by ALDH (this is secondary metabolite
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Why dont you see a primary alcohol in urine
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good substrate for ADH and is rapidly oxidzed to an aldehyde
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What does CYP2C9 mean
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2--family
C--subfamily 9--specific gene |
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What is require to be in same family
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>40% same family
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What is required to be in same subfamily
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>55 to be in same subfamily
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What is most important CYP450
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CYP3A (most amount of drugs
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What is CYP3A4 metabolize the most drugs
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largest active site, accomadtes both big and small drugs
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What do CYP 450 drug inhibitor do
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get into the active site, but are not metabolized--issue especially taking other drugs
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What do CYP 450 inducers do
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induce the making of more CYP450's, and metabolize drugs faster
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Is only after Phase II metabolism is the xenobiotic water solubility increased enough to make urinary elimination possible
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YES
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What are the 5 types of Phase II metabolism
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1. Glucuronidation
2. Sulfation 3.Glutathione 4. Glycine 5.Acetylation |
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What is the active form of glucronic acid for glucuronidation
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UDPGA
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What are some of the functional groups that UDPGA attack
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1. Phenols/Alcohols
2. Carboxcylic acids 3. Aromatic amines |
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What does UDPGA + alcohol/phenols form
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ether glucuronides
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What does UDPGA + carboxcylics form
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ESTER glucoronides
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What does UDPGA + aromatic amines form
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Amine Glucoronides
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How does a drug undergo sulfation
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by the active sulfate form
enzyme Sulfotransferase --cofactor PAPS/ |
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What is PAPS
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Phosphoadenosine
Phosphosulfate |
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What are some of functional groups that PAPS attack
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phenols
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What happens when you have high doses of a drug that can undergo sulfation/glucorondiation
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Glucorondiation predominates
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What happens when you have low doses of a drug that undergo sulfation/glucorondiation
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sulfation predominates
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What is enyzme and cofactor for Glutathione conjugation
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enzyme is Glutathion S Transferase (GST)
cofactor is (GSH) |
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What is GSH
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a tripeptide containing cysteine
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What does GSH attack
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attacks epoxides and arene oxides
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What are 2 pathway of acetaminophen
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converted by P450 to Quinone amine or by PAPS to sulfate conjugate
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What happens to the Quinone amine?
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converted by GSH to a Glutathione conjugate that is non toxic or converted to toxic metabolic
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Is GSH a protective conjuagte against potentially toxic epoxides and arene oxides
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YES
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What happens are the formation of Glutathione conjugate
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metabolized further to N-acetlycystein or mercapturic acid
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What is enzyme and Co-factor for Glycine conjugation
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enzyme is Glycine-N-actyltransferase, and co-factor is glycine
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What must happen 1st before
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must be active to its CoA thoiester
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What is functional group that glycine conjugates with
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Carboxcylic acids
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What enzymes and co-factors are required for acetylation
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enzyme: acetylase
cofactor: actyl coA |
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What fuctional groups does acetyl CoA attack
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armoatic amines
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What is the product of acetylation
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N-acetyl conjugate
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What are prodrugs
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pharmacologically inactive compounds that are converted to active drugs by enzymatic or chemical processes in the body
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The goal of a prodrug development is to
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overcome some problem associated with direct administration of the drug
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What are some problems overcome by prodrug development
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PPPUF TC
Poor absoprtion/distribution Poor aqueous solubility Poor patient aceeptance Unstable First-pass metabolism Toxicity Compliance issues |
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What is example of problem with absoption of ampicillin
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ampillicin is very water soluble,so add an ester to make more lipid solbule, and once into blood esterase converts to ampicillin
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What is an example of overcoming pt compliance issues
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Sustained release/depot forms
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How is haloperidol made sustained release
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ester added to phenol group, and long hydrocarbon chain alowing holoperiodl to released for about a mouth
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What is an example of problem with patient accepatance (tase) of sulfisoxazole
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add an N-actyl group of amide making the drug tasteless, anda then converted to active form by amidase in liver
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What is problem with aqeuous solubility
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need a balance of water/lipid solubility, if drug is too lipid soluble will be excreted
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Why else is important when drug have poor aqueous solublity
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cannot be formulated to IV
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What is an example of problem with poor aqeous solubility with methly prednisone
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not water soluble enough for injection, so addition of a carboxcillic acid, makes more water solulbe
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What drug is a drug subject to a high first pass metabolism
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naltrexone
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Why is naltrexone subject to such a high rate of 1st pass metabolism
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the pheonls by glucoronidation and sulfation
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How is the prodrug form of naltrexone better
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converting the phenol into an ester linakge slowing down its metabolism
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What is site-specfic delivery important
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if you want some drugs to cross the BBB or the skin or eye, and reduces side effects
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What is problem with site-speicifc delivery of dopamine
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is water soluble to cross teh BBB into the CNS
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What is the prodrug form of dopamine (L-Dopa) that allows it to cross teh BBB
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addtion of an amino acid, which makes it an analog of tyrosine, then is its TRANSPORTED by ACTIVE transport into BBB
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What is cyclophospamide a prodrug of
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nitrogen mustard
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What does the nitrogen mustard do
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very reactive, by crosslinking DNA
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What is the Sulfate conjugate highly water soluble of (sulfation)
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easily ionized, makes highly water solbule and inactive
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What happens after the formation of a Glucoronide
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either excreted by the kidneys as urine, excreted into the GI with Bile
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What happens when the Glucuronide is excreted into the GI with bile
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The B-glucurondiase in the the bacterial flora, are going to remove the glucorinic acid and reform the active drug
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Where does the active drug now go, after B-glucuronidase converts in gut
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enters the hepatic circulations
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