1. Metabolic Enzymes in Drug Absorption
Dr. Arthur G. Roberts

2. Blood Metabolites Drug Metabolism Absorption Non-enzymatic Drug
Excretion
Non-enzymatic
Distribution
Drug

4. GI Absorption
Gut Wall

5. Effects
Binders that are slow release. This is why generic drugs might behave differently than name brand.

6. Oral Dosage Products
Capsule versus tablet.

7. Factors Physicochemical Pharmaceutical Physicality
drug’s physical and chemical properties
Pharmaceutical
how a drug is manufactured
Physicality
routes of administration
what a drug deals with in the body

8. Physicality: Presystematic Metabolism
Liver
Extrahepatic CYPs
Digestion
Organs: Salivary gland, Pancreas, GI
Substrates: Sugars, Proteins, Lipids, Nucleic acids
Bacteria
Liver is associated with first pass metabolism.

9. Extrahepatic Cytochrome P450s: P450s Everywhere

10. Extrahepatic P450s: Skin

11. http://classes. midlandstech. com/carterp/Courses/bio211/chap23/chap23

12. Salivary and Pancreatic: a-Amylase
a-linked sugars
a-maltose
dextrin
Cofactor: Ca 2+

13. Sucrase http://en.wikipedia.org/wiki/Sucrase
Hydrolase-hydrolytic cleavage of Sucrose

14. Lactase

15. Dextrinase (a.k.a. Sucrase-isomaltase (SI))
starch SI
glycogen SI
a-glucose
dextrin
Sucrose intolerance

16. 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)

18. Stomach: Pepsin Prefers cleavage of hydrophobic AA F, W and Y pH 2.0
Porcine pepsin, Aspartate Proteases
acid-base mechanism
Aspartate abstracts proton from water
Hydroxyl attacks carbonyl generating a tetrahedral oxyanion intermediate
Rearangement of the intermediate leads to the product
Maximal activity at pH 2 (stomach 1-2)
Parietal-of, relating to, attached to or denoting the wall fo the body or of a body cavity or hollow structure.

19. Pancreatic Proteases

20. Specificity Carboxypeptidases Carboxypeptidase A – aromatic/aliphatic
Carboxypeptidases
Carboxypeptidase A – aromatic/aliphatic
Carboxypeptidase B – basic (Arginine/Lysine)

21. Role in Absorption: Peptide Drugs2
~Cys
Arg
Asp
Gly
Pro
Captopril
Trp
Exenatide
~Cys
Pro
Cys
Eptifibatide

22. Role in Absorption: Peptide Prodrugs

23. Liver

24. Mouth (Saliva): Lingual Lipase
Crystal Structure
Mechanism
Product

25. Stomach: Gastric Lipase
Mechanism
Product

26. Based on where they are located
Based on where they are located. What are the major differences between gastric and lingual lipase?
pH of the stomach 1-2
pH of the saliva

27. Role in Absorption: Activation of Lipid-based Prodrugs
Didanosine (HIV)
Adefovir dipivoxil (HIV)
Tenofovir disoproxil (HIV)

28. Role in Absorption: Lipid Excipients
Phospholipids
Polyglycerol fatty acid esters
Natural oils and fats
ipid Excipients in Self Emulsifying Drug Delivery Systems
Shivangi Saxena*, Haribansh Narayan Singh , Vipin Kumar Agrawal, Shashank Chaturvedi
Department of pharmaceutics, Invertis Institute of Pharmacy, Invertis University, Invertis Village, NH-24, Bareilly

29. http://classes. midlandstech. com/carterp/Courses/bio211/chap23/chap23

30. Ribonucleases and Deoxyribonucleases
Figure 2-E-5. The catalytic mechanism of RNase A, which contains two critical residues: His-12 and His-119. (a) The transition state is formed by electron transfer from His-12 to His-119, passing through 2'-OH. (b) After the transition state is formed, the electron can move from His-119 to His-12, generating the final product. DNA lacks the critical 2'-OH and thus cannot be catalyzed by RNase A.
Rnase A
Block absorption of DNA and RNA drugs
(electroporation or injection)

31. Nucleosidases Purine nucleosidase
Pyrimidine-5’-nucleotide nucleosidase

32. Phosphatases Cofactors: Zn2+ and Mg2+ Prefer High pH
Neutral pH in the stomach 6-7.4
pH optimum is 8-8.5
Intestinal Alkaline Phosphatase

33. Role in Absorption: Nucleoside Analogs
abacacir (HIV)
aciclovir (herpes)
azidothymidine (AZT)

34. Role in Absorption: Prodrugs

35. Bacteria http://www.ncbi.nlm.nih.gov/pubmed/7867662

39. nonalcoholic fatty-liver disease
obesity
see clpt a.pdf

40. (Dinnerware) http://en.wikipedia.org/wiki/Cyanuric_acid
(Dinnerware)

42. Less Effective Bacteria digoxin (heart drug) dihydrodigoxin
dihydrodigoxin decreased cardiac activity
reduction
Eubacterium Lentum
dihydrodigoxin

43. phenacetin Bacteria Phenetidine Liver P450 hemoglobin (Fe3+)
methemoglobinemia from abuse
decreased O2 binding
methemoglobinemia
acetominophen

44. End of Metabolic Enzymes in Drug Absorption