metabolic enzymes in drug absorption dr. arthur g. roberts
TRANSCRIPT
Factors
• Physicochemical– drug’s physical and chemical properties
• Pharmaceutical– how a drug is manufactured
• Physicality– routes of administration– what a drug deals with in the body
Physicality: Presystematic Metabolism
• Liver• Extrahepatic CYPs• Digestion– Organs: Salivary gland, Pancreas, GI– Substrates: Sugars, Proteins, Lipids, Nucleic acids
• Bacteria
Dextrinase (a.k.a. Sucrase-isomaltase (SI))
Sucrose intolerance
starch
a-glucose
glycogen
SI
SI
SI
dextrin
Role in Absorption
• Breakdown of excipients– corn, potato, sodium starch (amylase, dextrinase)– sodium starch glycolate (amylase, dextrinase)– starch pregelatinized (amylase, dextrinase)– lactose (lactase)– sucrose, confectioner sugar (sucrase)
Specificity
CarboxypeptidasesCarboxypeptidase A – aromatic/aliphaticCarboxypeptidase B – basic (Arginine/Lysine)
Role in Absorption: Peptide Drugs
Captopril
Eptifibatide
Pro
~Cys ArgGly
Asp
2
Trp
ProCys
~CysExenatide
Role in Absorption: Activation of Lipid-based Prodrugs
Didanosine (HIV)
Adefovir dipivoxil (HIV) Tenofovir disoproxil (HIV)
Role in Absorption: Lipid Excipients
• Phospholipids• Polyglycerol fatty acid esters• Natural oils and fats
Ribonucleases and Deoxyribonucleases
Rnase A
Block absorption of DNA and RNA drugs(electroporation or injection)
Liver P450
acetominophen
phenacetin
Bacteria
Phenetidine
methemoglobinemia
hemoglobin (Fe3+)
decreased O2 binding