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Individual Simulated Data WinNonLin Individual Simulated Data Reports

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

Lecture #15 Absorption

Absorption: Routes of Administration X 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

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

Pyloric Valve Sphincter of Oddi

Factors in GI Absorption Permeability and SA pH partition hypothesis

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

Factors that Influence Passive Diffusion: pH partition hypothesis

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

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

log P=0.07 (stomach and colon) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364820/ http://nurse-practitioners-and-physician-assistants.advanceweb.com/Features/Articles/Medication-Absorption-after-Gastric-Bypass-Surgery.aspx log P=0.07 (stomach and colon)

(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

Intestinal Absorption: Intestines rifampicin antibiotic (reduces absorption)

Stomach  Intestines Gastric Emptying (Limiting) Food (Especially Fat) http://www.austincc.edu/apreview/PhysText/Digestive.html

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 https://en.wikipedia.org/wiki/Remifentanil

Losses of Oral Bioavailability

Losses of Oral Bioavailability

Drug Metabolism

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

Extrahepatic Cytochrome P450s: P450s Everywhere

Extrahepatic P450s: Skin

Cytochromes P450

Cytochrome P450 3A4 FG FF FH http://www.cell.com/cms/attachment/601385/4739569/gr1b1.jpg http://www.sciencedirect.com/science/article/pii/S0165614709000388

Intestinal CYP3A4 Hepatic CYP3A4 CYTOCHROME P450 3A4

Weight Loss CYTOCHROME P450 3A4 INHIBITOR

Hepatic First Pass Metabolism FH and E 1 E

Hepatic First Pass Metabolism FH and E Low Metabolism High Metabolism

Saturable First Pass Metabolism Extraction Ratio and Bioavailability is Dose Dependent

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

Sugars http://classes.midlandstech.com/carterp/Courses/bio211/chap23/chap23.htm

Proteins

Lipids http://classes.midlandstech.com/carterp/Courses/bio211/chap23/chap23.htm

Nucleic Acids http://classes.midlandstech.com/carterp/Courses/bio211/chap23/chap23.htm

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

Helicobacter pylori Escherichia coli Staphylococcus aureus