Metabolic Enzymes in Drug Absorption

Dr. Arthur G. Roberts

2

Metabolites

Drug Metabolism

Excretion

Non-enzymatic

Distribution

Absorption

Blood

Drug

X

GI Absorption

Gut Wall

Effects

Oral Dosage Products

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

Extrahepatic Cytochrome P450s: P450s Everywhere

Extrahepatic P450s: Skin

Salivary and Pancreatic: a-Amylase

a-linked sugars

a-maltose

dextrin

Cofactor: Ca 2+

Sucrase

Lactase

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)

Stomach: Pepsin• Prefers cleavage of hydrophobic AA

• F, W and Y• pH 2.0

Pancreatic Proteases

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: Peptide Prodrugs

Liver

Mouth (Saliva): Lingual Lipase

Product

Crystal Structure Mechanism

Stomach: Gastric LipaseMechanism

Product

Based on where they are located. What are the major differences between gastric and lingual

lipase?

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)

Nucleosidases

Purine nucleosidase

Pyrimidine-5’-nucleotide nucleosidase

Phosphatases

Intestinal Alkaline Phosphatase

Cofactors: Zn2+ and Mg2+

Prefer High pH

Role in Absorption: Nucleoside Analogs

aciclovir (herpes) abacacir (HIV)

azidothymidine (AZT)

Role in Absorption: Prodrugs

Bacteria

obesity

nonalcoholic fatty-liver disease

(Dinnerware)

digoxin (heart drug)

dihydrodigoxin

BacteriaLessEffective

Liver P450

acetominophen

phenacetin

Bacteria

Phenetidine

methemoglobinemia

hemoglobin (Fe3+)

decreased O2 binding

End of Metabolic Enzymes in Drug Absorption