Drug metabolism - less common processes

• What is the focus of LV6 in drug metabolism?

  Less common processes.
• What type of enzymes are hydrolases?

  Enzymes that hydrolyse a wide variety of substrates.
• What role do hydrolases play in phase 1 metabolism?

  They are part of a minor pathway of phase 1 metabolism.
• Why are esters commonly used as pro-drugs?

  To promote administration of drugs including uptake through membranes by passive diffusion.
• What do carboxyl ester hydrolases (CES) catalyze?

  The hydrolysis of oxygen esters, converting esters to diols.
• What are ester hydrolases?

  Enzymes that hydrolyze esters in mammalian cells and drug crystals.
• In which family are most human ester hydrolases found?

  ACE2 or MCE2 family.
• What type of substrates do esterases tend to hydrolyze?

  Substrates with large acyl groups and small alcohols.
• Which substrates are hydrolyzed by carboxyl ester hydrolases (CES)?

  Substrates with large acyl groups and large alcohols.
• What is the importance of carboxylated ester pro-drugs?

  They are important for clearance and also in phase 2 renal elimination.
• How much can variations in rates for VETS vary?

  6-20 fold.
• What is poorly known about the variations in hydrolase activity?

  There is an autosomal chromosome polymorphism on 16p13.
• What is the significance of the 6 to 7A polymorphism at 16p13?

  It leads to differences in enzyme hydrolysis of many substrates.
• What effect does ethanol have on enzyme hydrolysis?

  It inhibits the hydrolysis of many substrates.
• What do sulfotransferases carry out?

  Sulphation reactions on endogenous substrates and xenobiotics.
• How are sulfotransferases related to each other?

  They are found in superfamilies related by sequence.
• What is true about the substrate profiles of sulfotransferases?

  They have distinct but overlapping substrate profiles.
• What type of substrates do SULTs act on?

  Phenol substrates.
• What type of substrates do SULTs also act on?

  Aliphatic alcohol substrates including steroid hormones.
• What type of substrates do SULTs rely on?

  Amine substrates.
• What is the status of some SULT substrates?

  Some substrates are unknown.
• What is the significance of sulfonation in phase 2 metabolism?

  It is the second most common reaction for nucleophilic drugs.
• Where does sulfonation commonly occur?

  In the liver, and also in the kidney and other organs.
• What is required for the formation of nucleophiles in sulfonation?

  ATP and a coenzyme.
• What does the original nucleophile form during sulfonation?

  SH, OH, or other nucleophile groups.
• What is the product of sulfonation?

  A sulfate ester, which is not really charged.
• What are the predominant conjugation processes at low and high drug concentrations?

  Sulfonation predominates at low drug concentrations and glucuronidation at high concentrations.
• What happens to sulfonate products from carboxylate groups?

  They are likely unstable and rapidly hydrolyze.
• What predominates at the carboxylate group?

  Glucuronidation predominates.
• What is the status of phosphorylation in drug metabolism?

  It is uncommon.
• What is required for phosphorylation to occur?

  A nucleophile group to react with labile phosphate.
• Why is phosphorylation important for certain drugs?

  It activates nucleotide analogue prodrugs to their corresponding nucleobase drugs.
• How can drugs be phosphorylated?

  They can be mono- or multiple phosphorylated.
• What is required for each phosphate group during phosphorylation?

  Separate enzymes are required for each phosphate group.