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Hepatic Clearance/1st Pass

Hepatic Clearance/1st Pass. Liver overview Hepatic clearance Hepatic extraction ratio Bioavailability and first pass metabolism Enterohepatic recirculation. Question.

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Hepatic Clearance/1st Pass

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  1. Hepatic Clearance/1st Pass • Liver overview • Hepatic clearance • Hepatic extraction ratio • Bioavailability and first pass metabolism • Enterohepatic recirculation

  2. Question • One drug a patient is taking is metabolized by CYP3A4 and the patient starts taking erythromycin (a CYP3A4 enzyme inhibitor), will the hepatic clearance of the first be altered?

  3. about 1500g 50-100k lobules blood flow: 1000-1500 ml/min metabolizes drugs excretes drugs into the bile Intestine Liver

  4. Liver Structure

  5. albumin Smooth ER Hepatocyte Drug Metabolism

  6. Clearance • Liver blood flow (Q or LBF) normally ranges between 1000-1500 mL/min or 60-90 L/hr • If asked to use in a calculation, we will use the mean of 1250 mL/min or 75 L/hr for normal liver blood flow

  7. Clearance Extraction ratio (ER) is a measure of efficiency of the liver at removing the drug from the bloodstream. It is highly variable and dependent on three factors: • intrinsic clearance (CLint) of the liver for the particular drug • fraction of the drug unbound (fup) • blood flow (Q)

  8. How to Calculate ER • If you can’t find ER directly, it can be calculate from other information that can be easily looked up for a particular drug: CLT and fe.

  9. Examples • CLT = 1400 ml/min and fe = 0.2 • CLT = 300 ml/min and fe = 0.8

  10. Classification of ER • ER > 0.7A “high ER” drug and therefore the liver is very efficient at removing the drug • 0.3 < ER < 0.7An “intermediate or moderate ER” drug and therefore the liver is moderately efficient at removing the drug • ER < 0.3A “low ER” drug and therefore the liver is not efficient at removing the drug

  11. Hepatic Extraction Ratio • fup - fraction of the drug unbound • CLint - intrinsic clearance • Q - blood flow

  12. Hepatic Clearance

  13. Venous Equilibration Model This equation can be simplified to see the determinants of hepatic clearance for low and high ER drugs individually.

  14. Low ER By definition a low ER drug has a ER < 0.3 and therefore the liver is inefficient at removing the drug from the blood.

  15. Low ER So the denominator of the VE equation can be reduced to Q: Simplified equation for low ER drugs

  16. High ER By definition a high ER drug has a ER > 0.7 and therefore the liver is very efficient at removing the drug from the blood.

  17. High ER So the denominator of the VE equation can be reduced to fup*CLint: Simplified equation for high ER drugs

  18. Determinants of Hepatic Clearance • For any drug? • For low ER drugs? • For high ER drugs?

  19. Alterations in the Determinants Clearance intrinsic (CLint) • Enzyme inducers increase the number of enzymes in the liver thus increasing Vmax, so CLint will increase. • Enzyme inhibitors in general competitively compete with the other drug for the same enzyme receptor. Therefore, the apparent Km is increased and CLint will decrease. • Liver disease can also produce a decrease in Vmax from tissue destruction thereby causing a decrease in CLint.

  20. Alterations in the Determinants Protein binding (fup) • Highly bound drugs can be displaced from protein binding sites by other drugs or other substances which will increase the fup • Alterations in the amount of the protein the drug is bound to will also change the fup • Malnutrition can cause decreases in albumin and therefore an increase in fup • Acute myocardial infarction can cause and increase in AAG and decrease fup

  21. Alterations in the Determinants Liver Blood Flow (Q) • Congestive Heart Failure (CHF) willdecrease Q • Food (especially high fat meals will cause a transient increase in Q • Certain drugs can alter Q by changing cardiac output

  22. Question • One drug a patient is taking is metabolized by CYP3A4 and the patient starts taking erythromycin (a CYP3A4 enzyme inhibitor), will the hepatic clearance of the first be altered?

  23. ORAL DRUG GUT PORTAL SYSTEMIC WALL VEIN CIRCULATION LIVER SITE OF ACTION GUT Bioavailability

  24. fa = fraction of drug absorbed from the GI tract F* = fraction of drug escaping first pass metabolism ER = hepatic extraction ratio Bioavailability (F)

  25. Bioavailability (F) How much of a 100 mg dose will make it into the systemic circulation if 75% of the dose is absorbed and 40% of the drug is removed with each pass through the liver?

  26. Enterohepatic Recirculation • In addition to metabolism the liver may remove drug from the blood by excretion of parent compound or metabolite into the bile. The bile is then secreted into the gallbladder and periodically released into the intestines. • The drug can then be reabsorbed back into the portal vein and again pass through the liver into the systemic circulation causing a secondary peak in the plasma concentration-time curve. • Generally large relatively polar molecules and examples include morphine, metoclopramide, irinotecan, digoxin, etc. • It is the basis for use of activated charcoal in overdoses after drug absorption is complete

  27. Enterohepatic Recirculation Cmax 2° peak Ln Cp time

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