phar 751 dietary effects on metabolism sarah brown, pharm.d. pharmacy practice resident asante...

PHAR 751 Dietary Effects on Metabolism

Sarah Brown, Pharm.D.Pharmacy Practice Resident

Asante Health Systemsbrown@asante.org

Metabolism: P-gp review

• Substrate + Inhibitor =

• Substrate + Inducer =

CYP Metabolism

• Cytochrome P450 – Gene superfamily: families subfamilies enzyme– Oxidative metabolism – Phase I– Location

• Liver• Small intestine

– Most abundant P450 is CYP3A4– Induction =– Inhibition =

Metabolism: CYP review

• Substrate + Inhibitor =

• Substrate + Inducer =

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

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

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

Another route of metabolism: FMO1

• Flavin-containing monooxygenase (FMO) 1 protein

• Oxidative metabolism

• Non-inducible

• Influenced by dietary intake

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

Metabolism & Diet

√ Food – protein

√ Drink – alcohol

next: citrus juices

Flavonoids

• Naturally occurring in citrus fruits

• Known for antioxidant activity

• Flavonoids– Flavone

• Flavanone• Flavonol

• Potential for drug-interactions

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.

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

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

Felodipine

• A dihydropyridine calcium channel blocker

• Reversibly competes w/ other CCBs for dhp-binding sites– Blocks voltage-

dependent Ca2+ currents in vascular smooth muscle

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.

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.

↓ 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.

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.

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.

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.

Thursday’s lecture 3/1/07

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.

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.

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

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.

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.

Benton, et al. Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolonged repolarization on the electrocardiogram. Clin Pharmacol Ther. 1996; 59: 383-8.

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.

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. 1997;52:139-145.

PK: Felodipine

PO felodipine w/ water

IV felodipine w/ GFJ

IV felodipine w/ water

PO felodipine w/ 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. 1997;52:139-145.

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. 1997;52:139-145.

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. 1997;52:139-145.

Hemodynamic data

Study: Felodipine & GFJ conclusions

• Metabolism of felodipine occurred in gut wall

• Increased plasma concentrations w/ oral felodipine & GFJ increase hemodynamic effects

Clinical Application

• GFJ: ↑ oral availability of commonly used medications

• Is the interaction significant?

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)

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.

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.

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.

Study conclusions

• Sufficient bergamottin and 6’,7’-dihydroxybergamottin concentrations

drug-interaction

• More furocoumarins? drug-interactions

Just in case…• Cyclosporine: Edwards et al. 6’,7’-dihydroxybergamottin in grapefruit

juice and Seville orange juice: Effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin Pharmacol Ther 1999;65(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 1998;54:753-60.

• Celiprolol: Lilja JJ, Juntti-Patinen L, Neuvonen PJ. Orange juice substantially reduces the bioavailability of the β-adrenergic-blocking agent celiprolol. Clin Pharmacol Ther 2004;75(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 2002;71(1):11-20.

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St John’s Wort

St John’s 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 John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 2001;70(4):317-26.

PK study: St John’s 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 John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 2001;70(4):317-26.

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 John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 2001;70(4):317-26.

PK study: St John’s wort & CYP

• Control: tolbutamide, caffeine, DM po, and versed IV, then oral versed 24 h later

• Short-term: 900mg St John’s wort then same as above, + 2nd dose of 900mg then St John’s wort x 14-15 additional days

• Long-term: 900mg St John’s wort then same as above, + 2nd dose of 900mg

PK study: St John’s wort & CYP

IV oral

□ before St John’s wort

○ after St John’s wort (short-term phase)

♦ after St John’s wort (long-term phase)

Short-term: no change

Long-term: 50% reduction in oral AUC and Cmax

PK data

Short-term: no change

Long-term: 50% reduction in oral AUC and Cmax

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 John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 2001;70(4):317-26.

Other outcomes

• Oral caffeine – CYP1A2 NS

• Oral tolbutamide – CYP2C9 NS

• Oral DM – CYP2D6 NS

• Interaction = CYP3A4

Study conclusions

• Induction of CYP3A by St John’s wort

• Long-term use ↓ efficacy of drugs metabolized by CYP3A

Lycopene

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 > raw)

Cohn et al. Comparative multiple dose plasma kinetics of lycopene administered in tomato juice, tomato soup or lycopene tablets. Eur J Nutr 2004;43:304-12.

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 2004;43:304-12.

Lycopene study

Cohn et al. Comparative multiple dose plasma kinetics of lycopene administered in tomato juice, tomato soup or lycopene tablets. Eur J Nutr 2004;43:304-12.

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 2004;43:304-12.

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