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.