MS Win Non Lin Assignment Due Today Simulated
- Slides: 32
MS Win. Non. Lin Assignment • Due Today: Simulated Table in MS Word (. docx) format. – You won’t have to do calculations, but understand what the terms mean.
Lecture #10 HEPATIC CLEARANCE
Outline • • Hepatic Blood Flow (QH) Liver Factors that Effect Hepatic Elimination Intrinsic Clearance Biliary Clearance Extraction Ratio Hepatic Clearance
Hepatic Blood Flow (QH) Heart fat skin Liver Hepatic Artery Hepatic Vein Gall Bladder Hepatic Portal Vein Bile Duct Hepatic Portal Vein Aorta Vena Cava GI Tract
Hepatic Blood Flow (QH) Heart fat skin Liver Hepatic Artery Hepatic Vein Gall Bladder Hepatic Portal Vein Bile Duct Hepatic Portal Vein Aorta Vena Cava GI Tract
Hepatic Blood Flow (QH) Heart fat skin Liver Hepatic Artery Hepatic Vein Gall Bladder Hepatic Portal Vein Bile Duct Hepatic Portal Vein Aorta Vena Cava GI Tract
Liver Lobes of Liver • 5 -8 – Right Lobe • 2 -3 – Left Lobe • 4 – Quadrate Lobe • 1 – Caudate Lobe
Liver Lobule Central Vein, Hepatic Vein or Hepatic Venule Liver acinus Central Vein, Hepatic Vein or Hepatic Venule Liver anicus #1 Portal Triad #2 #3
Liver acinus Bile canaliculus Septal Branch Central Vein, Hepatic Vein or Hepatic Venule Sinusoid Kupffer cell Hepatocyte Bile canaliculus Q Space of Disse Liver acinus Sinusoidal Lumen Hepatocyte Space of Disse Hepatocytes Kupffer cell Hepatic artery branch Portal vein branch Bile duct Stellate cell Pit cell Endothelial cell Dendritic with fenestrae cell (100 nm in diameter)
Liver Zones Liver acinus Central Vein, Hepatic Vein or Hepatic Venule Zone 1 Hepatic artery branch Portal vein branch Bile duct Zone 1 (Periportal) • nearest to the entering vascular supply • most oxygenated blood (insensitive to ischemic injury) • susceptible to viral hepatitis. • Specialized hepatocytes • gluconeogenesis • β-oxidation of fatty acids • cholesterol synthesis • haemochromatosis
Liver Zones Liver acinus Zone 3 Central Vein, Hepatic Vein or Hepatic Venule Zone 3 (Centrilobular) • Farthest from the entering vascular supply • least oxygenated blood (sensitive to ischemic injury) • Specialized hepatocytes • glycolysis • Lipogenesis • cytochrome P-450 -based drug detoxification (CYP 2 E 1) Hepatic artery branch Portal vein branch Bile duct
Liver Zones Liver acinus Central Vein, Hepatic Vein or Hepatic Venule Zone 2 (Midzonal) • Intermediate between 1 and 3 • Necrosis with Yellow Fever Hepatic artery branch Portal vein branch Bile duct
Factors that Affect Elimination • • • Perfusion (QH) Protein and Cell Binding Permeation/Transport Metabolism Secretion into Bile (Excretion)
Q Sinusoid 0. 025 L/hr Bile canaliculus 70 L/hr
Intrinsic Clearance • Book Version: intrinsic hepatocellular eliminating activity. Unbound drug • My Version: liver cell eliminating activity either through metabolism or excretion. metabolism excretory
Michaelis-Menten and Metabolic Intrinsic Clearance (CLint, m) Liver slow fast E+S ES P hepatic artery hepatic vein portal vein
v (mg/hr) Michaelis-Menten vs. Intrinsic Clearance
Biliary Clearance (CLbile) hepatocyte CLbile CLint, ex Bile canaliculus
Extraction Ratio Fraction Remaining Units = Unitless
Perfusion-Limited E > 0. 7 Non-Restrictive Capacity-Limited E < 0. 3 Restrictive Causes • Poor Drug Metabolism • Poor Drug Transport • Poor Drug Permeability
Extraction Ratios Restrictive (Capacity-Limited) Non-Restrictive (Perfusion-Limited)
Clearance, Extraction Ratio and Q E=~1 Non-Restrictive CLH (m. L/min) E > 0. 7 Restrictive E < 0. 3 QH (m. L/min)
Extraction Ratio (E) and fu Non-Restrictive
Liver Enzyme Activity
Modeling Hepatic Clearance Conc. along Liver Output Conc. after going through the liver
Well Stirred Model
Non-Restrictive (Perfusion-Limited) Hepatic Clearance: High Eh Can the hepatic clearance (CLH) be greater than hepatic blood flow (QH)?
Restrictive (Capacity-Limited) Hepatic Clearance: Low Eh
Complexities • Permeability • Location/Distribution of Transporters • Enterohepatic (Cycle) Circulation
Permeability barbital enalaprilat Hydrophobicity
Drug Transporters
Enterohepatic Circulation (Cycle) Heart fat skin Liver Hepatic Artery Hepatic Vein Gall Bladder Hepatic Portal Vein Bile Duct Hepatic Portal Vein Aorta Vena Cava GI Tract
- Think win-win example
- Win win win lose lose lose
- Win win situacija
- Assignment due today
- Assignment due today
- Assignment due today
- Liver blood supply
- Pac view
- Win-win negotiations are also known as
- Example of a win win situation
- Think win-win scenarios
- Habit 4
- Example of a lose lose situation
- Boulwarism negotiation
- Think win win habit 4 summary
- Win win nacin placanja
- Win win or no deal
- Today meeting or today's meeting
- We are going today
- Proposal kickoff meeting agenda
- Galton details
- Today's lesson or today lesson
- Example of repitition
- Homework due today
- Black cat analogy
- Reports due today
- Homework due today
- Astr 100 uiuc
- Homework due today
- 3 weeks from today
- Astr
- Homework due today
- Simulated annealing pseudocode