ADME 6 Flashcards
What is phase 2 metabolism regarded as?
true detoxifying pathway (with few exceptions)
•attenuates pharmacological activity and, thus, toxicity
what is a conjugation reaction?
attachment of polar endogenous molecules (except methylation and acetylation)to Phase I metabolites or parent drugs using transferase enzymes
what are the qualities of conjugation reactions?
more water-soluble and more readily excreted
what are the types of conjugation reactions that can occur?
glucuronide, sulphate, glycine, glutathione, methyl, acetyl
what do drugs with rapid first pass metabolism show?
poor oral bioavailability
what is the most common mode of phase two metabolism?
Glutathione
how is Glucuronic acid attachment achieved?
Xenobiotic (or Phase I) metabolite reacts with an activated form of glucuronic acid (UDPGA)
such as:-OH, -CO2H, -NH2, SH, rarely at C
what are the properties of Glucuronides
highly hydrophilic and water soluble
Conjugate is excreted in urine (MW < ~250) and/or bile (MW > ~350)
what is UDP glucuronosyltransferase?
is closely associated with CYP450Phase I metabolites are efficiently conjugated
what is Neonates?
refers to babes that have undeveloped liver UDP-glucuronosyltransferase activity, and may exhibit metabolic problem
what is Neonatal jaundice?
babes that may be attributable to their inability to conjugate bilirubin with glucuronic acid- go yellow ski n colour
what is glucuronic acid derived from?
D-glucose
what is the pka of the glucuronic acid ?
3.2- so nearly 100% ionized at physiological ph
how is the Coenzyme, UDP glucuronic acid synthesisied?
synthesised from reaction of glucuronic acid phosphate with uridine triphosphate
what is Uridine
Uridine is a glycoside (N-riboside of pyrimidine base uracil)
what is the orientation of the UDP leaving group?
UDP leaving group is aorientated -product is, therefore, b
Phosphate derivative as leaving group (most common natural O-glycosides are b)
what are the different types of Glucuronides?
O-Glucuronides•Most common : alcohol , phenol
S-Glucuronides•thiols(RSH, ArSH)
N-Glucuronides•amines, amides, sulfonamides
Di-glucuronicacid conjugates are very rareImproved hydrophilicity
what does Sulfate Conjugation lead to?
Leads to inactive, water-soluble metabolites
why does sulfate conjugation occur less frequently that glucoronidation?
Lower concentration of inorganic sulfates in mammals
•Fewer functional groups involved
•Occurs primarily with phenols
•Less commonly applies to alcohols, N-hydroxyls, thiols or (aromatic) amines
what is the final step in sulfate conjugation catalyzed by?
sulfotransferase enzymes
what can sulfate conjugates be hydrolyzed back to?
the parent by sulfatases
what happens in young children where glucuronyl transferase activity is not well developed?
O-sulfate conjugation predominates
what happens in sulfate conjugation?
inorganic sulfate + ATP= PAPS
Cytosolic reaction mediated by sulfotransferases, primarily SULT1 family isoforms
Sulfate conjugates are almost totally ionised-urine
Steroids eliminated biliary
what does amino acid conjugation lead to?
Leads to inactive, water-soluble metabolites
what forms when a carboxilic acid combines with amino acids?
it forms a peptide bond (amide)
what is the main amino acid conjugation?
Mainly glycine, (L-glutamine in primates)
where does amino acid conjugation mainly occur?
mitochondria of liver and kidney cells
what does amino acid conjugation need to work?
Requires initial activation of the carboxylic acid by acetyl-coenzyme A
Conjugation is then mediated by amino acid N-acyl transferase enzymes
what is Glutathione ?
a tripeptide present in most tissues
what happens in glutathione conjugation?
Thiol group reacts with electrophilic drugs to protect other cell nucleophiles (acts as a scavenger)
what may electrophillic chemicals cause?
–Carcinogenicity–Mutagenicity–Teratogenicity–Tissue necrosis
what is Methylation?
Minor pathway in the metabolism of drug molecules
•amines, alcohols, thiols
Reduces pharmacological activity
does methylation improve solubility?
Does not improve solubility (reduces polarity and hydrophilicity) except when it results in the formation of quaternary ammonium salts
Modulates activity of proteins and nucleic acids
•Involves S-adenosyl methionine(SAM) and a variety of methyl transferases
what is acetylation?
Important route for drugs with primary amino groups (aliphatic and aromatic)
what are the expectations of acetylation?
N-acetylprocainamideis as potent as the parent antiarrhythmic drug procainamide (different mode of action)
–N-acetylisoniazidis more toxic than the parent drug
how many steps is there in acetylation?
Acetylation is a two-step process
•Acetyl group is provided by acetyl-coenzyme A and catalysed by N-acetyltransferaseenzymes
whats more reactive, primary or secondary alcohols?
Primary alcohols are more reactive than secondary alcohols–less steric hindrance
what ways can Glucuronide Conjugation occur- attachments?
through alcohol/phenol/enol/carboxylic acid/ N-hydroxyl
