MS WinNonLin 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) Liver GI Tract Aorta Vena Cava Hepatic Artery Vein Portal Gall Bladder Bile Duct Heart skin fat 1 minute to get blood through the systemic circulation. See Table 4-4 in the textbook.

Hepatic Blood Flow (QH) Liver GI Tract Aorta Vena Cava Hepatic Artery Vein Portal Gall Bladder Bile Duct Heart skin fat

Hepatic Blood Flow (QH) Liver GI Tract Aorta Vena Cava Hepatic Artery Vein Portal Gall Bladder Bile Duct Heart skin fat

Liver Lobes of Liver 5-8 – Right Lobe 2-3 – Left Lobe http://healthfixit.com/location-and-pictures-of-different-organs-in-the-abdomen/ https://upload.wikimedia.org/wikipedia/commons/b/b7/2423_Microscopic_Anatomy_of_Liver.jpg https://en.wikipedia.org/wiki/Liver Lobes of Liver 5-8 – Right Lobe 2-3 – Left Lobe 4 – Quadrate Lobe 1 – Caudate Lobe

Liver Lobule Liver acinus Liver anicus Central Vein, Hepatic Vein or Hepatic Venule Liver acinus Central Vein, Hepatic Vein or Hepatic Venule Liver anicus http://illuminationstudios.com/archives/150/structure-of-a-hepatic-lobule #1 Portal Triad #2 #3

Liver acinus Q Liver acinus Bile duct Bile canaliculus Central Vein, Hepatic Vein or Hepatic Venule Sinusoid Septal Branch Space of Disse Hepatocyte Q Kupffer cell Hepatocyte Bile canaliculus Space of Disse Sinusoidal Lumen Kupffer cell http://www.nature.com/nrgastro/journal/v1/n2/fig_tab/ncpgasthep0055_F1.html http://www.nature.com/nri/journal/v6/n3/fig_tab/nri1784_F1.html http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774973/ Septal = Separating Branch http://www.solvobiotech.com/images/uploads/murine_hepatocita_011.jpg Hepatocytes Hepatocytes Hepatic artery branch Portal vein branch Bile duct Endothelial cell with fenestrae (100 nm in diameter) Dendritic cell Stellate cell Pit cell

Liver Zones Zone 1 Liver acinus Zone 1 (Periportal) Central Vein, Hepatic Vein or Hepatic Venule Zone 1 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 http://www.nature.com/nrgastro/journal/v1/n2/fig_tab/ncpgasthep0055_F1.html http://www.nature.com/nri/journal/v6/n3/fig_tab/nri1784_F1.html https://en.wikipedia.org/wiki/Lobules_of_liver http://vet.uga.edu/ivcvm/courses/vpat5215/digestive/week03/liverpath/liver1.htm Hepatic artery branch Portal vein branch Bile duct

Liver Zones Zone 3 Liver acinus Zone 3 (Centrilobular) Central Vein, Hepatic Vein or Hepatic Venule Zone 3 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 (CYP2E1) http://www.nature.com/nrgastro/journal/v1/n2/fig_tab/ncpgasthep0055_F1.html http://www.nature.com/nri/journal/v6/n3/fig_tab/nri1784_F1.html https://en.wikipedia.org/wiki/Lobules_of_liver http://vet.uga.edu/ivcvm/courses/vpat5215/digestive/week03/liverpath/liver1.htm Hepatic artery branch Portal vein branch Bile duct

Liver Zones Zone 2 Liver acinus Zone 2 (Midzonal) Central Vein, Hepatic Vein or Hepatic Venule Zone 2 Zone 2 (Midzonal) Intermediate between 1 and 3 Necrosis with Yellow Fever http://www.nature.com/nrgastro/journal/v1/n2/fig_tab/ncpgasthep0055_F1.html http://www.nature.com/nri/journal/v6/n3/fig_tab/nri1784_F1.html https://en.wikipedia.org/wiki/Lobules_of_liver http://vet.uga.edu/ivcvm/courses/vpat5215/digestive/week03/liverpath/liver1.htm 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 70 L/hr 0.025 L/hr Bile canaliculus http://courses.washington.edu/conj/bess/bile/bile.html http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748197/pdf/WJG-14-5641.pdf (620 ml/day) ~25 ml/hr 0.025 L/hr 0.025 L/hr Bile canaliculus

Intrinsic Clearance Book Version: intrinsic hepatocellular eliminating activity. My Version: liver cell eliminating activity either through metabolism or excretion. Unbound drug http://www.ncbi.nlm.nih.gov/pubmed/9561488 metabolism excretory

Michaelis-Menten and Metabolic Intrinsic Clearance (CLint,m) Liver fast slow E+S ES  P hepatic artery hepatic vein portal vein Show the derivation of the Michaelis-Menten Equation:

Michaelis-Menten vs. Intrinsic Clearance is the capacity of endogenous enzymes to transform a substance expressed in volume per unit time, since formation of the metabolite is rate limiting for its elimination. The Clint decreases as substrate increases because we are talking about a volume cleared. More substrate means that it takes more time to clear the volume. https://apps.simcyp.com/Mobile/Features.aspx http://www.xenoblis.com/services/metabolism/intrinsic-clearance/ v (mg/hr)

Biliary Clearance (CLbile) hepatocyte CLint,ex CLbile Bile canaliculus

Extraction Ratio Fraction Remaining Units = Unitless

Perfusion-Limited E > 0.7 Non-Restrictive Capacity-Limited http://www.boomer.org/c/p4/c17/c1704.html E < 0.3 Restrictive Causes Poor Drug Metabolism Poor Drug Transport Poor Drug Permeability

Extraction Ratios Restrictive Non-Restrictive (Capacity-Limited) (Perfusion-Limited)

Clearance, Extraction Ratio and Q Non-Restrictive E=~1 E > 0.7 CLH (mL/min) Restrictive E < 0.3 QH (mL/min)

Extraction Ratio (E) and fu Non-Restrictive Restrictive

Liver Enzyme Activity

Modeling Hepatic Clearance Output Conc. after going through the liver Conc. along Liver Concentration along the length of liver. Output concentration. From Intrinsic Clearance Lecture Fall 2014 (Slide 22) Not sure

Well Stirred Model 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

barbital Permeability Hydrophobicity enalaprilat

Drug Transporters

Enterohepatic Circulation (Cycle) Liver GI Tract Aorta Vena Cava Hepatic Artery Vein Portal Gall Bladder Bile Duct Heart skin fat Figure 2-10 in the book.