Review of Intestinal Drug Absorption and Intestinal Drug ...

PHAR 751 Dietary Effects on Metabolism Sarah Brown, Pharm.D. Pharmacy Practice Resident Asante Health System [email protected] 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% t 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 crosstolerance 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 voltagedependent 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. Thursdays 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

x7d 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;52:139145. 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. 1997;52:139145. 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;52:139145. 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;52:139145. 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 M GFJ; 5 M SOJ) 6,7-dihyroxybergamottin (10-60 (23) M GFJ; 36 M SOJ) Bergapten (31 M 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 6,7dihydroxybergamottin 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 -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. http://www.theage.com.au/ffximage/2007/02/04/svWAVE_wideweb__470x371,0.jpg St Johns Wort 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 2001;70(4):317-26.

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

IV before St Johns wort after St Johns wort (short-term phase) after St Johns wort (long-term phase) oral 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 Johns 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 Johns 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

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