Grapefruit: Inhibits CYP3A4

Edwards, et al. Drug Metab. Disp. 24:1287, 1996.

dihydroxybergamottin

FFP 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 100-280% when coadministered with grapefruit juice, compared with water.

Grapefruit Juice

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

Terfenadine Midazolam

Saquinavir Triazolam

Cyclosporin Verapamil

Grapefruit: Inhibits CYP3A4

Rau et al., Clin Pharmacol Ther 61:401, 1997.

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 Css of CYP3A4 substrates for low-E parenteral and all-E oral; e.g.:

•indinavir

•cyclosporin

•combined oral contraceptives

Vitamins

PyridoxineReduces Css of phenytoin and phenobarbital

Folic AcidReduces Css 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, Css for all orally administered drugs that are CYP1A2 substrates.

Smoking Tobacco

CYP1A2 is induced. Significantly reduces AUC, Css 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, 1996.

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

Pathology relevant to PKVascular

•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.

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.

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.

Pathology relevant to PKProtein 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.

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

Css

Css,u

F DM/Ko CLint,u

fup

High-E parenteral

Css

Css,u

F DM/Ko QH

fup

albumin: fup

enzyme activity: CLint,u

blood flow and shunting: QH

t1/2

CL

CLint

CLint,u

fup

V

QH

Case Study: Ceftriaxone

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

Ceftriaxone – plasma protein binding

Group [n]KA,eq

[M-1 x 10-4]

nP[M-1 x 10-4]

fup

Normal [8]3.91 ± 0.62

5.90 ± 0.46

0.050 ± 0.008

Fatty Liver[5]

3.52 ± 0.35

5.11 ± 0.89

0.071 ± 0.021*

Cirrhosis[4]

3.20 ± 0.35

4.56 ± 0.88

0.091 ± 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]

Vss

[L/kg]

t1/2

[hr]

fe

[%]

Normal0.226 ± 0.064

0.142 ± 0.017

8.4 ± 1.82 45.8 ± 6.8

Fatty Liver0.207 ± 0.036

0.129 ± 0.022

9.7 ± 1.26 50.6 ± 10.6

Cirrhosis0.235 ± 0.106

0.109 ± 0.035

8.0 ± 1.98 68.3 ± 14.8

Cirrhosis w/ ascites

0.390 ± 0.156*

0.288 ± 0.077*

9.7 ± 1.83 74.7 ± 3.9*

* = Different from Normal, p < 0.05

Ceftriaxone – PK Parameters

CLu

[mL/min/kg]

CLR,u

[mL/min/kg]CLNR,u

[mL/min/kg]

Normal 4.59 ± 1.29 2.04 ± 0.46 2.55 ± 0.94

Fatty Liver 3.19 ± 0.71 1.58 ± 0.47 1.61 ± 0.45

Cirrhosis 2.70 ± 0.93* 1.84 ± 0.720.87 ± 0.48*

Cirrhosis w/ ascites

2.06 ± 0.85* 1.55 ± 0.670.52 ± 0.20*

* = Different from Normal, p < 0.05

Summary – Liver Disease

CL, both renal and hepatic.

May require DR.

FFP for high-E drugs given p.o. due to shunting and CLint,u.

May require DR.

fup for albumin-bound drugs.

DR for high-E via parenteral route.