P3: Pharmacokinetic journey Flashcards
What happens in phase II reactions?
Prepare functionally activated compounds for excretion in the bile/urine.
Conjugation of xenobiotic w/ 1 of a variety of diff compounds.
Results in a pharmacologically inactive soluble compound.
Catalysed by diff enzymes.
What enzyme does glucuronidation use?
UDP-glucuronyltransferase.
What functional groups undergo glucuronidation?
OH
COOH
NH2
SH
What enzyme does sulphation use?
Sulphotransferase
What functional groups undergo sulphation?
OH
NH2
SO2 NH2
What enzyme does methylation use?
Methyltransferase
What functional groups undergo methyltransferase?
OH
NH2
What enzyme does glutathione conjugation use?
Gluthatione-S-transferase
What functional groups undergo glutathione conjugation?
Epoxide
Organic halides
What occurs in glucuronidation?
Glucuronic acid transferred from high energy phosphate compound UDP-GA to e- rich atom (N, O, S)
What happens in sulfate conjugation?
Addition of SO3^- to drug.
Major pathway for phenols and can occur in alcohols, amines and occasionally thiols.
Requires energy rich donor compound (PAPS).
Enzyme relatively non-specific - metabolise wide range of drugs. Mostly phenols, lesser extent alcohols.
What happens if there is a lack of sulfate at higher doses?
Glucuronidation will predominate
What does the enzyme glutathione S-transferase do?
Glutathione exists as thiolate anion when bound to GST.
GST catalyses the nucleophilic addition of thiolate anion to electrophilic centres in xenobiotics.
What does glutathione conjugation generate?
A less toxic compound that is modified to a mercapturic acid derivative that is excreted.
What happens if there is an overexpression of glutathione in cancer?
Form of drug resistance - may be due to overexpression of GST or increased lvls of glutathione. Drugs given with buthionine sulfoximine.
