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

Grapefruit Juice Selective post-translational down regulation of CYP3A4 in intestine and liver increases F FP for: TerfenadineMidazolam SaquinavirTriazolam CyclosporinVerapamil

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

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

Vitamins Pyridoxine Reduces C ss of phenytoin and phenobarbital Folic Acid Reduces C ss of phenytoin, but not phenobarbital Ascorbic Acid Competitively inhibits sulfate conjugation; 1 g/d  60%  in F for ethyinyl estradiol

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

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

Smoking Tobacco CYP2C9 & -19 not induced. Phenytoin

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

Dosing Regimen Individualization Liver Disease

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, Westphal and Brogard. Drug Administration in Chronic Liver Disease. Drug Safety 17:47-73, 1997.

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. Q H decreased in cirrhosis, but no change or increased in hepatitis. For high-E drugs, F FP is elevated and CL H is decreased; e.g., meperidine, pentazocine, propranolol.

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

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 V E (normal = 8L) by 1-20 L, with an average of about 4 L. Renal Function Changes GFR reduced in cirrhosis w/ ascites.

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 f up. 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.

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

S/A Diagrams Oral & low-E parenteral C ss C ss,u F DM/  K o CL int,u f up High-E parenteral C ss C ss,u F DM/  K o QHQH f up  albumin:  f up  enzyme activity:  CL int,u  blood flow and shunting:  Q H

t 1/2 CL CL int CL int,u f up V QHQH

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

Ceftriaxone – plasma protein binding Group [n] K A,eq [M -1 x ] nP [M -1 x ] f up Normal [8]3.91 ± ± ± Fatty Liver [5] 3.52 ± ± ± 0.021* Cirrhosis [4] 3.20 ± ± ± 0.020* Cirrhosis w/ ascites [6] 2.13 ± 0.50*3.39 ± 0.84*0.161 ± 0.061* * = Different from Normal, p < 0.05

Ceftriaxone – PK Parameters CL [mL/min/kg] V ss [L/kg] t 1/2 [hr] f e [%] Normal0.226 ± ± ± ± 6.8 Fatty Liver0.207 ± ± ± ± 10.6 Cirrhosis0.235 ± ± ± ± 14.8 Cirrhosis w/ ascites ± 0.156*0.288 ± 0.077*9.7 ± ± 3.9* * = Different from Normal, p < 0.05

Ceftriaxone – PK Parameters CL u [mL/min/kg] CL R,u [mL/min/kg] CL NR,u [mL/min/kg] Normal4.59 ± ± ± 0.94 Fatty Liver3.19 ± ± ± 0.45 Cirrhosis2.70 ± 0.93*1.84 ± ± 0.48* Cirrhosis w/ ascites 2.06 ± 0.85*1.55 ± ± 0.20* * = Different from Normal, p < 0.05

Summary – Liver Disease  CL, both renal and hepatic. May require  DR.  F FP for high-E drugs given p.o. due to shunting and  CL int,u. May require  DR.  f up for albumin-bound drugs.  DR for high-E via parenteral route.