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Grapefruit: Inhibits CYP3A4

Grapefruit: Inhibits CYP3A4. F FP of high-E drugs is significantly elevated when given with grapefruit juice. Frozen concentrate has more pronounced effect than fresh squeezed juice. dihydroxybergamottin. Edwards, et al. Drug Metab. Disp. 24:1287, 1996.

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Grapefruit: Inhibits CYP3A4

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  1. Grapefruit: Inhibits CYP3A4 FFP of high-E drugs is significantly elevated when given with grapefruit juice. Frozen concentrate has more pronounced effect than fresh squeezed juice. dihydroxybergamottin Edwards, et al. Drug Metab. Disp. 24:1287, 1996. Bioavailability of felodipine and nifedipine increase 100-280% when coadministered with grapefruit juice, compared with water.

  2. Grapefruit Juice Selective post-translational down regulation of CYP3A4 in intestine and liver increases FFP for:

  3. Grapefruit: Inhibits CYP3A4 Differential block shunts more TF to carboxylate and elevates TF, which is cardiotoxic. Rau et al., Clin Pharmacol Ther 61:401, 1997.

  4. St. John’s Wort • Herbal remedy used to treat depression • Potent inducer of CYP3A4 • Reduces the AUC and Css of CYP3A4 substrates for low-E parenteral and all-E oral; e.g.: • indinavir • cyclosporin • combined oral contraceptives

  5. Vitamins

  6. Charcoal-broiled food CYP1A2 is induced. Significantly reduces AUC, Css for all orally administered drugs that are CYP1A2 substrates.

  7. CYP1A2 is induced. Significantly reduces AUC, Css for CYP1A2 substrates. Smoking Tobacco Theophylline Hunt, Jusko, Yurchak. Clin Pharmacol Therap 19:549

  8. CYP2C9 & -19 not induced. Smoking Tobacco Phenytoin

  9. Alcohol • Acute: (co-administration; “binge drinking”) • Competitive inhibition of drug metabolism Chronic: prolonged heavy use • Induces CYP2E1: acetaminophen, theophylline are example substrates • Induces glucuronyl transferase • Confounding variable: liver disease Depletion of glutathione in liver by alcohol makes liver more susceptible to acetaminophen damage

  10. Dosing Regimen Individualization Liver Disease

  11. Liver Disease or Involvement AIDS Cirrhosis Acute & Chronic Hepatitis: A, B, and C Biliary Tract: infection, gall stones Cancer: liver, biliary tree Drug-Induced Liver Disease Welling and Pool. Effect of liver disease on drug metabolism and pharmacokinetics. Ch. 16 in Drug Induced Hepatotoxicity, Cameron RG, et al., Eds. Springer-Verlag, 1996. Westphal and Brogard. Drug Administration in Chronic Liver Disease. Drug Safety 17:47-73, 1997.

  12. Pathology relevant to PK • Vascular • fibrotic infiltration elevates resistance to blood flow, and extrahepatic collateral veins develop (shunts). Up to 60% of hepatic flow may bypass the liver. • QH decreased in cirrhosis, but no change or increased in hepatitis. • For high-E drugs, FFP is elevated and CLH is decreased; e.g., meperidine, pentazocine, propranolol.

  13. Pathology relevant to PK • Hepatic Cell Mass • moderate cirrhosis • severe cirrhosis •  hepatitis • Intrinsic Hepatocyte Function •  severe cirrhosis •  viral and alcoholic hepatitis CLint,u may or may not be affected.

  14. Pathology relevant to PK • Ascites • Lymph in peritoneal cavity due to increased retention of Na and fluid by kidneys, and elevated hepatic blood pressure. • Increases VE (normal = 8L) by 1-20 L, with an average of about 4 L. • Renal Function Changes • GFR reduced in cirrhosis w/ ascites.

  15. Pathology relevant to PK • Protein Synthesis • Liver is the site of synthesis of albumin and 1-AAG. • Decreased rate of albumin synthesis is common, which causes reduced plasma concentration of albumin and elevated fup. • Some liver diseases increase the synthesis rate of 1-AAG, although cirrhosis seems to decrease its synthesis rate. So 1-AAG concentration in plasma may increase, decrease, or not change.

  16. Liver Function Tests • Not useful as guides to alter DR. • Bilirubin • Albumin • Prothrombin Time • Enzymes, e.g.: • alkaline phosphatase • aspartate aminotransferase

  17. fup Css Css F DM/ Ko F DM/ Ko CLint,u QH Css,u Css,u fup albumin: fup  enzyme activity: CLint,u  blood flow and shunting: QH S/A Diagrams High-E parenteral Oral & low-E parenteral

  18. QH t1/2 CL V CLint fup CLint,u

  19. Case Study: Ceftriaxone Stoeckel, Tuerk, Trueb, McNamara. Clin. Pharmacol. Therap. 36:500, 1984

  20. Ceftriaxone – plasma protein binding * = Different from Normal, p < 0.05

  21. Ceftriaxone – PK Parameters * = Different from Normal, p < 0.05

  22. Ceftriaxone – PK Parameters * = Different from Normal, p < 0.05

  23. Summary – Liver Disease

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