PHAR 751 Dietary Effects on Metabolism

1
PHAR 751 Dietary Effects on Metabolism

• Sarah Brown, Pharm.D.
• Pharmacy Practice Resident
• Asante Health System
• sbrown_at_asante.org

2
Metabolism P-gp review

• Substrate Inhibitor
• Substrate Inducer

3
CYP Metabolism

• Cytochrome P450
• Gene superfamily families? subfamilies? enzyme
• Oxidative metabolism Phase I
• Location
• Liver
• Small intestine
• Most abundant P450 is CYP3A4
• Induction
• Inhibition

4
Metabolism CYP review

• Substrate Inhibitor
• Substrate Inducer

5
Metabolism Diet

• Food
• Macronutrients
• Protein
• CHO
• Fats
• Micronutrients
• Vitamins
• Minerals
• Indoles
• Drink
• Grapefruit juice
• Orange juice
• Seville orange juice
• Alcohol

• ? Diet can alter enzyme activity ? influence the
  intensity duration of action

6
Macronutrients Protein Intake

• 20 of diet
• Malnutrition contributes to variability in drug
  metabolism
• CYP-mediated
• In rats CYP3A activity ? from 18 to 1 w/
  ?protein intake
• CYP1A2 ? w/ 0.5 protein diet
• CYP1A1 no change

7
Protein intake theophylline metabolism

• CYP-mediated
• ? in Cl of 30 when reduce protein intake from
  20 to 10
• ? t½ from 8-9 h to 6 h by increasing protein from
  10 to 40.
• TPN patients ? lower plasma Cl

8
Another route of metabolism FMO1

• Flavin-containing monooxygenase (FMO) 1 protein
• Oxidative metabolism
• Non-inducible
• Influenced by dietary intake

9
Micronutrient Indole effect on metabolism

• Indole-3-carbinol (I3C)
• Naturally-occurring chemical found in cruciferous
  vegetables
• Induces CYP1A1
• Inhibits FMO1
• Also marketed as dietary supplement

Katchamart, et al. Concurrent flavin-containing
monooxygenase down-regulation and cytochrome
p-450 induction by dietary indoles in rat
implications for drug-drug interaction. Drug
Metabolism and Disposition 2000 28 (8) 930
936.
10
Influence of dietary I3C on FMO1 protein levels
Katchamart, et al. Concurrent flavin-containing
monooxygenase down-regulation and cytochrome
p-450 induction by dietary indoles in rat
implications for drug-drug interaction. Drug
Metabolism and Disposition 2000 28 (8) 930
936.
11
FMO (-) and CYP ()
Katchamart, et al. Concurrent flavin-containing
monooxygenase down-regulation and cytochrome
p-450 induction by dietary indoles in rat
implications for drug-drug interaction. Drug
Metabolism and Disposition 2000 28 (8) 930
936.
12
Micronutrient Indole effect on metabolism of
tamoxifen
Katchamart, et al. Concurrent flavin-containing
monooxygenase down-regulation and cytochrome
p-450 induction by dietary indoles in rat
implications for drug-drug interaction. Drug
Metabolism and Disposition 2000 28 (8) 930
936.
13
Why do we care?

• Clinical relevance
• Drug-drug or drug-food interactions
• Potential for altered toxicity of drugs that are
  substrates for FMO and CYP
• Potential altered efficacy (i.e. tamoxifen)
• I3C DIM dietary supplements

14
Alcohol Tobacco effects on metabolism

• 80 95 alcoholics smoke (25 30
  non-alcoholics smoke)
• 70 are heavy smokers
• Those who drink smoke ? more cigarettes/day
• Correlation between alcohol intake tobacco use
• Association w/ environmental and genetic factors?

Schoedel KA, Tyndale RF. Induction of
nicotine-metabolizing CYP2B1 by ethanol and
ethanol-metabolizing CYP2E1 by nicotine summary
and implications. Biochimica et Biophysica Acta
1619 (2003) 283 290.
15
Alcohol Nicotine types of tolerance

• Tolerance
• Cross tolerance
• Functional cross-tolerance
• Metabolic cross-tolerance

Schoedel KA, Tyndale RF. Induction of
nicotine-metabolizing CYP2B1 by ethanol and
ethanol-metabolizing CYP2E1 by nicotine summary
and implications. Biochimica et Biophysica Acta
1619 (2003) 283 290.
16
Alcohol Nicotine metabolism

• Alcohol
• Primarily by ADH
• 20 by CYP2E1 (up to 60 at high BAC)
• Nicotine
• Metabolized by CYP2A6 (and CYP2B6 in humans
  CYP2B1 in rats )? cotinine (inactive)

Schoedel KA, Tyndale RF. Induction of
nicotine-metabolizing CYP2B1 by ethanol and
ethanol-metabolizing CYP2E1 by nicotine summary
and implications. Biochimica et Biophysica Acta
1619 (2003) 283 290.
17
CYP2E1

• CYP2E1
• Also metabolizes APAP, isoniazid, tamoxifen,
  halothane
• Inducible by both EtOH nicotine
• Potential for altering efficacy of clinically
  used substrates

Schoedel KA, Tyndale RF. Induction of
nicotine-metabolizing CYP2B1 by ethanol and
ethanol-metabolizing CYP2E1 by nicotine summary
and implications. Biochimica et Biophysica Acta
1619 (2003) 283 290.
18
Alcohol Nicotine CYP2E1 ?

• ? expression of CYP2E1 (induced by nicotine and
  EtOH)
• ? metabolism of EtOH metabolic cross-tolerance
• ? more EtOH required for same effect
  tolerance

Schoedel KA, Tyndale RF. Induction of
nicotine-metabolizing CYP2B1 by ethanol and
ethanol-metabolizing CYP2E1 by nicotine summary
and implications. Biochimica et Biophysica Acta
1619 (2003) 283 290.
19
Study in rats

• Up-regulation of brain CYP2B1 CYP2E1 by EtOH
• ? Nicotine metabolized by CYP2B1 metabolic
  cross tolerance

Schoedel KA, Tyndale RF. Induction of
nicotine-metabolizing CYP2B1 by ethanol and
ethanol-metabolizing CYP2E1 by nicotine summary
and implications. Biochimica et Biophysica Acta
1619 (2003) 283 290.
20
Metabolism Diet

• v Food protein
• v Drink alcohol
• next citrus juices

21
Flavonoids

• Naturally occurring in citrus fruits
• Known for antioxidant activity
• Flavonoids
• Flavone
• Flavanone
• Flavonol
• Potential for drug-interactions

22
PK Study Felodipine Grapefruit juice

• Substrate felodipine
• Enzyme inhibitor grapefruit juice
• Inhibits CYP3A4 CYP1A2
• What happens to felodipine concentrations?

Lown et al. Grapefruit Juice Increases Felodipine
Oral Availability in Humans by Decreasing
Intestinal CYP3A Protein Expression. J Clin
Invest. 1997 99(19) 2545-2553.
23
Naringin

• A flavonoid
• Metabolized to the flavonone, naringenin
• bitter component of grapefruit juice
• 800 mg/L
• 100 g flesh 200 mL regular strength juice
• Inhibits CYP3A4 CYP1A2

24
Quercetin

• A Flavonol
• Average daily intake 16 25 mg/day
• Adjunct to cisplatin, cyclophosphamide, and
  adriamycin tx
• Chelates metal ions acts as free radical
  scavenger
• ? CAD mortality ? stroke incidence
• Dietary supplementation 1 1.5 g/day
• Known to inhibit oxidation of nifedipine and
  felodipine

25
Felodipine

• A dihydropyridine calcium channel blocker
• Reversibly competes w/ other CCBs for dhp-binding
  sites
• Blocks voltage-dependent Ca2 currents in
  vascular smooth muscle

26
Felodipine Grapefruit juice

• Study Recurrent administration of grapefruit
  juice felodipine kinetics
• Hypothesis continuous administration of
  grapefruit juice ? increased intestinal CYP3A4 ?
  diminishing effect on felodipine kinetics

Lown et al. Grapefruit Juice Increases Felodipine
Oral Availability in Humans by Decreasing
Intestinal CYP3A Protein Expression. J Clin
Invest. 1997 99(19) 2545-2553.
27
CYP3A4 concentration in study participants

• Drop in the CYP3A4 enterocyte concentration in
  all subjects

Lown et al. Grapefruit Juice Increases Felodipine
Oral Availability in Humans by Decreasing
Intestinal CYP3A Protein Expression. J Clin
Invest. 1997 99(19) 2545-2553.
28
? CYP3A4 following GFJ administration
Lown et al. Grapefruit Juice Increases Felodipine
Oral Availability in Humans by Decreasing
Intestinal CYP3A Protein Expression. J Clin
Invest. 1997 99(19) 2545-2553.
29
All CYPs? Or just 3A4?
no consistent change in the level of enterocyte
CYP2D6 or CYP1A1 protein with recurrent
grapefruit juice ingestion.
Lown et al. Grapefruit Juice Increases Felodipine
Oral Availability in Humans by Decreasing
Intestinal CYP3A Protein Expression. J Clin
Invest. 1997 99(19) 2545-2553.
30
Clinical interactions felodipine GFJ

• ? after 5 days GFJ tid
• ? after first glass GFJ
• ? Water

Lown et al. Grapefruit Juice Increases Felodipine
Oral Availability in Humans by Decreasing
Intestinal CYP3A Protein Expression. J Clin
Invest. 1997 99(19) 2545-2553.
31
Conclusion Felodipine Grapefruit juice

• Study Recurrent administration of grapefruit
  juice felodipine kinetics
• Hypothesis continuous administration of
  grapefruit juice ? increased intestinal CYP3A4 ?
  diminishing effect on felodipine kinetics
• Result decrease in intestinal CYP3A4 in all
  subjects

Lown et al. Grapefruit Juice Increases Felodipine
Oral Availability in Humans by Decreasing
Intestinal CYP3A Protein Expression. J Clin
Invest. 1997 99(19) 2545-2553.
32
Thursdays lecture 3/1/07
33
Terfenadine

• Second-generation H1-receptor antagonist
• Rapidly and almost completely metabolized by
  CYP3A4
• Active metabolite
• Cardiotoxic drug-drug interactions w/
  erythromycin and ketoconazole

Benton, et al. Grapefruit juice alters
terfenadine pharmacokinets, resulting in
prolonged repolarization on the
electrocardiogram. Clin Pharmacol Ther. 1996 59
383-8.
34
PK study Terfenadine Grapefruit juice

• Study Is bioavailability of terfenadine enhanced
  by GFJ?
• Does timing of terfenadine dose and
  administration of GFJ matter?

Benton, et al. Grapefruit juice alters
terfenadine pharmacokinets, resulting in
prolonged repolarization on the
electrocardiogram. Clin Pharmacol Ther. 1996 59
383-8.
35
PK study Terfenadine Grapefruit juice

• Primary endpoints QT prolongation, AUC, Cmax,
  Tmax
• 60 mg terfenadine bid x 7d
• 240 mL GFJ w/ terfenadine x 7d
• OR 240 mL GFJ 2 h after terfenadine dose x 7 d
• EKG and plasma level on day 7 and day 14

36
PK study Terfenadine Grapefruit juice
A Simultaneous GFJ administration B GFJ 2
hours after terfenadine
Benton, et al. Grapefruit juice alters
terfenadine pharmacokinetics, resulting in
prolonged repolarization on the
electrocardiogram. Clin Pharmacol Ther. 1996 59
383-8.
37
PD Terfenadine Grapefruit juice
A Simultaneous GFJ administration B GFJ 2
hours after terfenadine
Benton, et al. Grapefruit juice alters
terfenadine pharmacokinetics, resulting in
prolonged repolarization on the
electrocardiogram. Clin Pharmacol Ther. 1996 59
383-8.
38
Benton, et al. Grapefruit juice alters
terfenadine pharmacokinetics, resulting in
prolonged repolarization on the
electrocardiogram. Clin Pharmacol Ther. 1996 59
383-8.
39
PK study Terfenadine GFJ conclusions

• PK interaction Increases terfenadine
  concentration in some subjects
• Effect more pronounced when administered together
• Delayed effect likely d/t rapid absorption of
  terfenadine
• Interaction occurs in gut wall CYP3A enzymes
• ? concentration ? increase in QTc interval on EKG

Benton, et al. Grapefruit juice alters
terfenadine pharmacokinetics, resulting in
prolonged repolarization on the
electrocardiogram. Clin Pharmacol Ther. 1996 59
383-8.
40
Another study Felodipine, water, grapefruit juice

• PK of IV and PO felodipine
• Grapefruit juice or water 15 min prior to dose of
  felodipine
• 10 mg ER tablet or 1.5 mg IV over 60 min
• Measured SBP, DBP, and HR

Lundahl J, Regardh CG, Edgar B, Johnsson G.
Effects of grapefruit juice ingestion
pharmacokinetics and haemodynamics of
intravenously and orally administered felodipine
in healthy men. Eur J Clin Pharmacol.
199752139-145.
41
PK Felodipine
? IV felodipine w/ water
?IV felodipine w/ GFJ
? PO felodipine w/ GFJ
? PO felodipine w/ water
Lundahl J, Regardh CG, Edgar B, Johnsson G.
Effects of grapefruit juice ingestion
pharmacokinetics and haemodynamics of
intravenously and orally administered felodipine
in healthy men. Eur J Clin Pharmacol.
199752139-145.
42
PK data
Lundahl J, Regardh CG, Edgar B, Johnsson G.
Effects of grapefruit juice ingestion
pharmacokinetics and haemodynamics of
intravenously and orally administered felodipine
in healthy men. Eur J Clin Pharmacol.
199752139-145.
43
Hemodynamic effects in relation to PK

• Oral felodipine GFJ ? ? DBP (12 19 mmHg) ?
  HR
• Effects were similar for IV felodipine w/ water
  GFJ

Lundahl J, Regardh CG, Edgar B, Johnsson G.
Effects of grapefruit juice ingestion
pharmacokinetics and haemodynamics of
intravenously and orally administered felodipine
in healthy men. Eur J Clin Pharmacol.
199752139-145.
44

• Hemodynamic data

45
Study Felodipine GFJ conclusions

• Metabolism of felodipine occurred in gut wall
• Increased plasma concentrations w/ oral
  felodipine GFJ ? increase hemodynamic effects

46
Clinical Application

• GFJ ? oral availability of commonly used
  medications
• Is the interaction significant?

47
(No Transcript)
48
Grapefruit juice Seville Orange juice

• Furocoumarins
• Bergamottin (16 µM GFJ 5 µM SOJ)
• 6,7-dihyroxybergamottin (10-60 (23) µM GFJ 36
  µM SOJ)
• Bergapten (31 µM SOJ only)

49
Study Seville Orange juice, GFJ, felodipine

• Juice ? equimolar concentration
• Single dose felodipine
• Seville orange juice
• Dilute GFJ
• Common orange juice ? (-) control
• Hypothesis furocoumarins are involved in the
  grapefruit juice interaction

Malhotra et al. Seville orange juice-felodipine
interaction Comparison with dilute grapefruit
juice and involvement of furocoumarins. 2001
69(1)14-23.
50
Conc vs. time - felodipine
Malhotra et al. Seville orange juice-felodipine
interaction Comparison with dilute grapefruit
juice and involvement of furocoumarins. 2001
69(1)14-23.
51
PK data felodipine
PK data following a single dose of felodipine
taken with 8 ounces SOJ, GFJ, or OJ
Malhotra et al. Seville orange juice-felodipine
interaction Comparison with dilute grapefruit
juice and involvement of furocoumarins. 2001
69(1)14-23.
52
Study conclusions

• Sufficient bergamottin and 6,7-dihydroxybergamot
  tin concentrations
• ? drug-interaction
• More furocoumarins?
• ? drug-interactions

53
Just in case

• Cyclosporine Edwards et al. 6,7-dihydroxybergam
  ottin in grapefruit juice and Seville orange
  juice Effects on cyclosporine disposition,
  enterocyte CYP3A4, and P-glycoprotein. Clin
  Pharmacol Ther 199965(3) 237-44.
• Pranidipine Hashimoto et al. Interaction of
  citrus juices with pranidipine, a new
  1,4-dihydropyridine calcium antagonist, in
  healthy subjects. Eur J Clin Pharmacol
  199854753-60.
• Celiprolol Lilja JJ, Juntti-Patinen L, Neuvonen
  PJ. Orange juice substantially reduces the
  bioavailability of the ß-adrenergic-blocking
  agent celiprolol. Clin Pharmacol Ther
  200475(3)184-90.
• Fexofenadine Dresser et al. Fruit juices inhibit
  organic anion transporting polypeptide-mediated
  drug uptake to decrease the oral availability of
  fexofenadine. Clin Pharmacol Ther
  200271(1)11-20.

54
http//www.theage.com.au/ffximage/2007/02/04/svWAV
E_wideweb__470x371,0.jpg
55
St Johns Wort
56
St Johns Wort

• Known CYP3A4 induction
• Reports of interactions with
• Theophylline (CYP1A2)
• Amitriptyline ((CYP2D6, CYP1A2)
• Warfarin (CYP2C9)
• Digoxin (p-gp substrate)

Wang et al. The effects of St Johns wort
(Hypericum perforatum) on human cytochrome P450
activity. Clin Pharmacol Ther 200170(4)317-26.
57
PK study St Johns wort CYP

• Interaction at the level of CYP?
• Which CYPs are involved?
• Induction? Inhibition?
• Three part study (control, short-term dosing,
  long-term dosing)

Wang et al. The effects of St Johns wort
(Hypericum perforatum) on human cytochrome P450
activity. Clin Pharmacol Ther 200170(4)317-26.
58
Study drugs

• Tolbutamide (CYP2C9)
• Caffeine (CYP2A1)
• Dextromethorphan (CYP2D6)
• Oral midazolam (intestinal wall and hepatic
  CYP3A)
• IV midazolam (hepatic CYP3A)

Wang et al. The effects of St Johns wort
(Hypericum perforatum) on human cytochrome P450
activity. Clin Pharmacol Ther 200170(4)317-26.
59
PK study St Johns wort CYP

• Control tolbutamide, caffeine, DM po, and versed
  IV, then oral versed 24 h later
• Short-term 900mg St Johns wort then same as
  above, 2nd dose of 900mg then St Johns wort x
  14-15 additional days
• Long-term 900mg St Johns wort then same as
  above, 2nd dose of 900mg

60
PK study St Johns wort CYP
IV oral

• Short-term no change
• Long-term 50 reduction in oral AUC and Cmax

? before St Johns wort ? after St Johns wort
(short-term phase) ? after St Johns wort
(long-term phase)
61
PK data

• Short-term no change
• Long-term 50 reduction in oral AUC and Cmax

62
Study drugs

• Tolbutamide (CYP2C9)
• Caffeine (CYP2A1)
• Dextromethorphan (CYP2D6)
• Oral midazolam (intestinal wall and hepatic
  CYP3A)
• IV midazolam (hepatic CYP3A)

Wang et al. The effects of St Johns wort
(Hypericum perforatum) on human cytochrome P450
activity. Clin Pharmacol Ther 200170(4)317-26.
63
Other outcomes

• Oral caffeine CYP1A2 ? NS
• Oral tolbutamide CYP2C9 ? NS
• Oral DM CYP2D6 ? NS
• Interaction CYP3A4

64
Study conclusions

• Induction of CYP3A by St Johns wort
• Long-term use ? ? efficacy of drugs metabolized
  by CYP3A

65
Lycopene
66
Lycopene

• 80 of dietary lycopene from tomatoes and tomato
  products
• Most abundant carotenoid in human plasma
• Evidence for beneficial effects ? preventing
  prostate cancer
• Availability from tomatoes is improved with
  processing (puree gt raw)

Cohn et al. Comparative multiple dose plasma
kinetics of lycopene administered in tomato
juice, tomato soup or lycopene tablets. Eur J
Nutr 200443304-12.
67
Lycopene study

• Lycopene depletion phase
• Each group 20mg lycopene daily x 8d
• Three tx groups
• Juice
• Soup
• Tablet

Cohn et al. Comparative multiple dose plasma
kinetics of lycopene administered in tomato
juice, tomato soup or lycopene tablets. Eur J
Nutr 200443304-12.
68
Lycopene study
Cohn et al. Comparative multiple dose plasma
kinetics of lycopene administered in tomato
juice, tomato soup or lycopene tablets. Eur J
Nutr 200443304-12.
69
Lycopene concentration juice vs. soup vs. tablet
Cohn et al. Comparative multiple dose plasma
kinetics of lycopene administered in tomato
juice, tomato soup or lycopene tablets. Eur J
Nutr 200443304-12.
70
Conclusions

• Processing releases lycopene for absorption
• Also causes conversion to all-E-lycopene, the
  most stable configuration
• 8 days of tomato product double the average
  concentration from baseline