2. Remote Desktop: WinNonLin

3. Individual Simulated Data
WinNonLin
Individual Simulated Data
Reports

4. WinNonLin Single and Multiple Patients PK: Plasma, Urine, Feces
PD Response
Absorption/Systemic Exposure
Bioavailability
Bioequivalence

5. Lecture #15
Absorption

6. Absorption: Routes of AdministrationX
Enteral (GI Tract)
oral, sub-lingual, buccal, rectal
Parenteral (injection/infusion)
Not IV or IA
IM, SC, ID
Skin (Patch)
Lungs
Inhalation
Vaginal (local)
Eye (local)
IP = intraperitoneal,
IT = intrathecal (into the spinal canal) i

7. Absorption: Routes of Administration
(between ribs)
(back of neck)
(butt) IM
(back)
(shoulder)
(cerebral spinal fluid)

8. Pyloric Valve
Sphincter of Oddi

9. Factors in GI Absorption
Permeability and SA
pH partition hypothesis

10. Transport Across a Membrane
Permeability
Surface Area
Scenario 1
Scenario 1
Scenario 3 SA SA P SA P
[Drug]
[Drug] P
[Drug] P
Increase [Drug]
Increase SA

11. Factors that Influence Passive Diffusion: pH partition hypothesis

12. GI Absorption 32m2 (60 L/hr) 2m2 Organ SA (m2) Oral Cavity 0.0197
Esophagus
0.0235
Stomach
0.05 (9 L/hr)
water

13. Most Absorption Occurs in the Intestine
log P=0.27
stomach acid inhibitor
[Drug]plasma

14. log P=0.07 (stomach and colon)
log P=0.07 (stomach and colon)

15. (arthritis)
log P = -4.3
log P = -3.1
(osteoporosis)
log P = -2.1
log P = 1.13
(antibiotics)
log P = -6.4
(benzodiazepine antidote)
log P = 1.00

16. Intestinal Absorption: Intestines
rifampicin
antibiotic (reduces absorption)

17. Stomach  Intestines Gastric Emptying (Limiting) Food (Especially Fat)

18. Side Matters Right Side Down Stomach Left Side Down Stomach
duodenum
pyloric valve
Left Side Down
Stomach
duodenum
pyloric valve
pyloric valve
opioid analgesic
X gastric emptying

19. Losses of Oral Bioavailability

20. Losses of Oral Bioavailability

21. Drug Metabolism

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

23. Extrahepatic Cytochrome P450s: P450s Everywhere

24. Extrahepatic P450s: Skin

25. Cytochromes P450

26. Cytochrome P450 3A4 FG FF FH

27. Intestinal CYP3A4
Hepatic CYP3A4
CYTOCHROME P450
3A4

28. Weight Loss
CYTOCHROME P450
3A4 INHIBITOR

29. Hepatic First Pass Metabolism FH and E1 E

30. Hepatic First Pass Metabolism FH and E
Low Metabolism
High Metabolism

31. Saturable First Pass Metabolism
Extraction Ratio and Bioavailability is Dose Dependent

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

33. Sugars

34. Proteins

35. Lipids

36. Nucleic Acids

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

38. Helicobacter pylori
Escherichia coli
Staphylococcus aureus