ADME 6

Question 1

What is phase 2 metabolism regarded as?

Answer 1

true detoxifying pathway (with few exceptions)

•attenuates pharmacological activity and, thus, toxicity

Question 2

what is a conjugation reaction?

Answer 2

attachment of polar endogenous molecules (except methylation and acetylation)to Phase I metabolites or parent drugs using transferase enzymes

Question 3

what are the qualities of conjugation reactions?

Answer 3

more water-soluble and more readily excreted

Question 4

what are the types of conjugation reactions that can occur?

Answer 4

glucuronide, sulphate, glycine, glutathione, methyl, acetyl

Question 5

what do drugs with rapid first pass metabolism show?

Answer 5

poor oral bioavailability

Question 6

what is the most common mode of phase two metabolism?

Answer 6

Glucuronic acid attachment

Question 7

how is Glucuronic acid attachment achieved?

Answer 7

Xenobiotic (or Phase I) metabolite reacts with an activated form of glucuronic acid (UDPGA)
such as:-OH, -CO2H, -NH2, SH, rarely at C

Question 8

what are the properties of Glucuronides

Answer 8

highly hydrophilic and water soluble

Conjugate is excreted in urine (MW < ~250) and/or bile (MW > ~350)

Question 9

what is UDP glucuronosyltransferase?

Answer 9

is closely associated with CYP450Phase I metabolites are efficiently conjugated

Question 10

what is Neonates?

Answer 10

refers to babes that have undeveloped liver UDP-glucuronosyltransferase activity, and may exhibit metabolic problem

Question 11

what is Neonatal jaundice?

Answer 11

babes that may be attributable to their inability to conjugate bilirubin with glucuronic acid- go yellow ski n colour

Question 12

what is glucuronic acid derived from?

Answer 12

D-glucose

Question 13

what is the pka of the glucuronic acid ?

Answer 13

3.2- so nearly 100% ionized at physiological ph

Question 14

how is the Coenzyme, UDP glucuronic acid synthesisied?

Answer 14

synthesised from reaction of glucuronic acid phosphate with uridine triphosphate

Question 15

what is Uridine

Answer 15

Uridine is a glycoside (N-riboside of pyrimidine base uracil)

Question 16

what is the orientation of the UDP leaving group?

Answer 16

UDP leaving group is aorientated -product is, therefore, b

Phosphate derivative as leaving group (most common natural O-glycosides are b)

Question 17

what are the different types of Glucuronides?

Answer 17

O-Glucuronides•Most common : alcohol , phenol
S-Glucuronides•thiols(RSH, ArSH)
N-Glucuronides•amines, amides, sulfonamides
Di-glucuronicacid conjugates are very rareImproved hydrophilicity

Question 18

what does Sulfate Conjugation lead to?

Answer 18

Leads to inactive, water-soluble metabolites

Question 19

why does sulfate conjugation occur less frequently that glucoronidation?

Answer 19

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

Question 20

what is the final step in sulfate conjugation catalyzed by?

Answer 20

sulfotransferase enzymes

Question 21

what can sulfate conjugates be hydrolyzed back to?

Answer 21

the parent by sulfatases

Question 22

what happens in young children where glucuronyl transferase activity is not well developed?

Answer 22

O-sulfate conjugation predominates

Question 23

what happens in sulfate conjugation?

Answer 23

inorganic sulfate + ATP= PAPS
Cytosolic reaction mediated by sulfotransferases, primarily SULT1 family isoforms
Sulfate conjugates are almost totally ionised-urine
Steroids eliminated biliary

Question 24

what does amino acid conjugation lead to?

Answer 24

Leads to inactive, water-soluble metabolites

Question 25

what forms when a carboxilic acid combines with amino acids?

Answer 25

it forms a peptide bond (amide)

Question 26

what is the main amino acid conjugation?

Answer 26

Mainly glycine, (L-glutamine in primates)

Question 27

where does amino acid conjugation mainly occur?

Answer 27

mitochondria of liver and kidney cells

Question 28

what does amino acid conjugation need to work?

Answer 28

Requires initial activation of the carboxylic acid by acetyl-coenzyme A
Conjugation is then mediated by amino acid N-acyl transferase enzymes

Question 29

what is Glutathione ?

Answer 29

a tripeptide present in most tissues

Question 30

what happens in glutathione conjugation?

Answer 30

Thiol group reacts with electrophilic drugs to protect other cell nucleophiles (acts as a scavenger)

Question 31

what may electrophillic chemicals cause?

Answer 31

–Carcinogenicity–Mutagenicity–Teratogenicity–Tissue necrosis

Question 32

what is Methylation?

Answer 32

Minor pathway in the metabolism of drug molecules
•amines, alcohols, thiols
Reduces pharmacological activity

Question 33

does methylation improve solubility?

Answer 33

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

Question 34

what is acetylation?

Answer 34

Important route for drugs with primary amino groups (aliphatic and aromatic)

Question 35

what are the expectations of acetylation?

Answer 35

N-acetylprocainamideis as potent as the parent antiarrhythmic drug procainamide (different mode of action)
–N-acetylisoniazidis more toxic than the parent drug

Question 36

how many steps is there in acetylation?

Answer 36

Acetylation is a two-step process

•Acetyl group is provided by acetyl-coenzyme A and catalysed by N-acetyltransferaseenzymes

Question 37

whats more reactive, primary or secondary alcohols?

Answer 37

Primary alcohols are more reactive than secondary alcohols–less steric hindrance

Question 38

what ways can Glucuronide Conjugation occur- attachments?

Answer 38

through alcohol/phenol/enol/carboxylic acid/ N-hydroxyl