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Critical review of the literature

2014-2015

Sophie Argon, Pharm D

Drug Interaction Database Program

Senior Editor, Drug Interactions

e-PKGene Project Manager

18th International Conference on Drug-Drug Interactions

Seattle, June 29th – July 1st 2015

1

Outline

1- DDI Publications: What is new in

2014-2015?Publications: updates and trends

Most pronounced drug interactions

Transporter-based clinical DDIs

2- 2014-2015 Highlight:Case study: Grapefruit juice-clopidogrelinteraction 2

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Number of publications entered in DIDB

3

0

100

200

300

400

500

600

700

800

464434

510472

522547

504463 460

487

600625

701 696731

109

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840

Top 10 journalsmake up 47% of the published articles

JournalsNumber of

Articles

Overall

PercentageMain focus

Drug Metab Dispos 117 13.9 in vitro

Xenobiotica 49 5.8 in vitro

J Clin Pharmacol 39 4.6 in vivo

Int J Clin Pharmacol Ther 38 4.5 in vivo

Br J Clin Pharmacol 28 3.3 in vivo

Cancer Chemother Pharmacol 27 3.2 in vivo

Clin Ther 27 3.2 in vivo

Antimicrob Agents Chemother 25 3.0 in vitro/in vivo

Drug Metab Pharmacokinet 25 3.0 in vitro/in vivo

Clin Drug Investig 23 2.7 in vivo4

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Types of publications* (2010-2014)

5

354

220

122

366

257

139

351337

178

345

304

244

357 348

249

0

50

100

150

200

250

300

350

400

in vivo in vitro metabolism in vitro transport

2010 2011 2012 2013 2014

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*publications can contain both in vitro and in vivo studies

Publications 2014-2015

840 publications

in vivo:

46% publications in vitro: 54% publications

Enzymes (58%)

Metabolism 34%

CYPs (31%)

UGTs (8%)

Inhibition 47.4%

CYPs (43%)

UGTs (9%)

Activation 1.3%

UGTs (3%) CYPs (2%)

Induction 17.3%

CYPs (23%)

UGTs (3%)

Transporters (42%)

Substrates 47.2%

P-gp (25%)

OATs (19%)

OATPs (10%)

Inhibition 52.8%

P-gp (36%)

OATs (19%)

OATPs (8%)

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Publications 2014-2015

840 publications

in vivo: 46% publications

inhibition (52%)

Positive Studies 43.5%

Inhibitors:

11% Antibiotics

10% Antivirals

9.5% Antifungals

Negative

Studies 56.5%

single drug PK (33%)

including organ impairment

food-effect studies

induction (15%)

Positive Studies 67.3%

Inducers:

39.4% Antibiotics (rifampin)

25.7% Antivirals

18.2% Anticonvulsant (carbamazepine)

Negative

Studies 32.7%

in vitro:

54% publications

7

38 case reports of toxicity

victims involved

8

Therapeutic classes Immunosuppressants: cyclosporine, tacrolimus

most represented: Anticoagulants: warfarin

Cancer treatments: methotrexate

18.4

13.1 13.1

10.5

7.8

5.2 5.2 5.2 5.2

Pe

rce

nta

ge

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38 case reports of toxicity

perpetrators involved

9

Therapeutic classes Anticonvulsants: phenytoin

most represented: Cardiovascular drugs: various

Antibiotics: rifampin

13.1 13.110.5 10.5 10.5

5.2 5.2 5.2P

erc

en

tag

e

Outline

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1- DDI Publications: What is new in2014-2015?Publications: updates and trendsMost pronounced drug interactionsTransporter-based clinical DDIs

2- 2014-2015 Highlight:Case study: Grapefruit juice-clopidogrelinteraction

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TOP 10 inhibitory interactions

Victims InhibitorsEnzymes/

Transporters

Victim

AUC ratio Reference

dextromethorphan fluoxetine CYP2D6 27.2 Sager, 2014

voclosporin ketoconazole CYP3A, P-gp 18.1 Ling, 2014

asunaprevir rifampin (SD, P.O) OATP1B1, OATP2B1 14.8 Eley, 2015

dextromethorphan quinidine CYP2D6 14.3 Bosilkovska, 2014

almorexant ketoconazole CYP3A4 10.7 Dingemanse, 2014

maraviroc telaprevir CYP3A, P-gp,

OATP1B1

9.3 Vourvahis, 2014

omeprazole fluvoxamine and

voriconazole

CYP2C19, 3A4 7.8 Bosilkovska, 2014

omeprazole fluoxetine CYP2C19 7.1 Sager, 2014

pitavastatin rifampin (SD, IV) OATP1B1 6.5 Prueksaritanont, 2014

nebivolol paroxetine CYP2D6 6.2 Briciu, 2014

11All perpetrators are potent inhibitors of CYPs enzymes and/or transporters.

All victims are sensitive substrates or probes

TOP 10 induction interactionsVictims Inducers Enzymes

Victim AUC

ratioReference

midazolam rifampin CYP3A4 0.04 Bosilkovska, 2014

bosutinib rifampin CYP3A4 0.08 Abbas, 2015

omeprazole rifampin CYP2C19 0.10 Bosilkovska, 2014

voclosporin rifampin CYP3A4 0.12 Ling, 2014

erlotinib rifampin CYP3A4, 1A2, 2C8 0.24 Hamilton, 2014

apremilast rifampin CYP3A4 0.28 Liu, 2014

pretomanib rifampin CYP3A, other 0.32 Dooley, 2014

etonogestrel efavirenz CYP3A4 0.36 Vieira, 2014

bupropion rifampin CYP2B6 0.40 Bosilkovska, 2014

dolutegravir tipranavir and

ritonavir

CYP3A4, UGT 0.41 Song, 2014

The most pronounced inductions are almost all due to rifampin.12

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Outline

1- DDI Publications: What is new in2014-2015?Publications: updates and trendsMost pronounced drug interactionsTransporter-based clinical DDIs

2- 2014-2015 Highlight: Case study: Grapefruit juice-clopidogrelinteraction

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In vivo articles discussing the role of

transporters in DDI (128 studies)

14

P-gp

40%

OATP1B1

13%

OATP1B3

8%OATP2B1

5%

OATP1A2

2%

OATP

2%

MATE1

6%

MATE2-K

2%

OAT3

6%

OAT1

5%

BCRP

3%OCT

3%

OCT2

2%OCT1

2%

MRP2

1% OCTN1

1%

Percent of studies

OATPs: 30%

OATs: 11%

MATE1/2-K: 8%

OCTs: 7%

BCRP: 3%

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P-gp related inhibition

Victim Precipitant Precipitant DoseVictim AUC

ratioReference

voclosporin (also CYP3A S) ketoconazole 400 mg QD [10 days] 18.13 Ling, 2014

maraviroc (also CYP3A S) telaprevir 750 mg TID [10 days] 9.32 Kim, 2014

domperidone (also CYP3A S) milk thistle 500 mg BID [6.5 days] 4.88 Yamsani, 2014

ticagrelor (also CYP3A S) cyclosporine 600 mg SD 2.85 Teng, 2014

voclosporin (also CYP3A S) verapamil 80 mg TID [10 days] 2.68 Ling, 2014

loperamide quinidine 600 mg SD 2.18 Kim, 2014

fexofenadine* quinidine 200 mg SD 2.14 Bosilkovska, 2014

teneligliptine ketoconazole 400 mg QD [6 days] 1.5 Nakamaru, 2014

digoxin* ivacaftor 150 mg BID [9 days] 1.32 Robertson, 2015

lenvatinib rifampin 600 mg SD 1.3 Shumaker, 2014

canagliflozin cyclosporine 400 mg SD 1.25 Devineni, 2015

loperamide HM30181** 180 mg SD 1.25 - 1.58 Kim, 2014

afatinib ritonavir 200 mg BID [3 days] 1.21 - 1.47 Wind, 2014

digoxin* voclosporin 0.4 mg/kg BID [11 days] 1.25 Ling, 2014

colchicine (also CYP3A S) atorvastatin 40 mg QD [14 days] 1.24 Davis, 2014

digoxin* vandetanib 300 mg SD 1.22 Johansson, 2014

ethinyl estradiol ledipasvir 90 mg QD [14 days] 1.2 German, 2014

15* Regulatory agencies recommended P-gp probe substrates

** HM30181 is a third generation P-gp inhibitor

Hepatic OATP-related inhibition

Victim Perpetrator Perpetrator DoseVictim AUC

ratioTransporter(s) involved Reference

asunaprevir rifampin 600 mg SD 14.8 OATP, OATP1B1, OATP2B1 Eley, 2015

maraviroc* telaprevir 750 mg TID [10 days] 9.32 P-gp, OATP1B1 Vourvahis, 2014

pitavastatin rifampin600 mg SD (IV)

600 mg SD (PO)

6.65

5.41OATP1B1

Prueksaritanont,

2014

rosuvastatin rifampin 600 mg SD (PO) 4.08 OATP1B1Prueksaritanont,

2014

bosentan clarithromycin 500 mg BID [4 days] 3.73 OATP1B1, OATP1B3 Markert, 2014

rosuvastatin rifampin 600 mg SD (IV) 3.03 OATP1B1Prueksaritanont,

2014

(S)-fexofenadine* rifampin 450 mg QD [7 days] 2.99 P-gp, OATPs, OATP1B3 Akamine, 2015

(R)-fexofenadine* rifampin 450 mg QD [7 days] 2.98 P-gp, OATPs, OATP1B3 Akamine, 2015

empagliflozin gemfibrozil 600 mg BID [5 days] 1.6 OATP1B1, OATP1B3, OAT3 Macha, 2014

rosuvastatin asunaprevir 200 mg BID [11 days] 1.4OATP1B1, OATP2B1,

OATP1B3Eley, 2015

rosuvastatinelvitegravir and

cobicistat

150/150 mg QD

[10 days]1.4 BCRP, OATP1B1, OATP1B3 Custodio, 2014

empagliflozin rifampin 600 mg SD 1.35 OATP1B1, OATP1B3 Macha, 2014

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*Also a P-gp substrate

Maraviroc and telaprevir: interplay between inhibition of CYP3A/P-gp and OATP1B1 by telaprevir

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Intestinal OATP-related inhibition

Victim Perpetrator Perpetrator DoseVictim AUC

ratio

Transporter(s)

involvedReference

nadolol green tea 700 mL [14 days] 0.15 OATP1A2 Misaka, 2014

(S)-fexofenadine apple juice 400 mL SD 0.35 OATP2B1 Akamine, 2014

(R)-fexofenadine apple juice 400 mL SD 0.47 OATP2B1 Akamine, 2014

talinolol quercetin 20 mg BID, 6 days

Day 7: 1500 mg with

talinolol

0.76 P-gp, OATP2B1,

OATP1A2

Nguyen, 2014

talinolol quercetin 500 mg TID, 6 days

Day 7: 1500 mg with

talinolol

0.78 P-gp, OATP2B1,

OATP1A2

Nguyen, 2014

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DDI publications 2014-2015:

conclusion

• Most pronounced interactions

Inhibition: various CYP and transporters involved

Induction: mostly due to rifampin

• Case reports of toxicity

Victim drugs: immunosuppressants, anticoagulants,

cancer treatments

Perpetrators: anti-infective agents, anticonvulsants,

cardiovascular drugs

• Transporter-based DDIs

P-gp and OATPs are the main transporters involved.18

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Outline

1- DDI Publications: What is new in2014-2015?Publications: updates and trendsMost pronounced drug interactionsTransporter-based clinical DDIs

2- 2014-2015 Highlight: Case study: Grapefruit juice-clopidogrelinteraction

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Case study: Grapefruit juice-

clopidogrel interaction

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Clin Pharmacol Ther. 2014 Mar;95(3):307-13.

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Grapefruit juice-clopidogrel interactionStudy Design & Drug Administration

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Study design & subjects:

Random crossover

14 healthy volunteers (CYP2C19: 7 EMs; 5 IMs; 2 PMs), non-smokers

Victim: clopidogrel (P2Y12 platelet inhibitor)

600 mg single dose, administered in the morning on Day 3 of

grapefruit juice or water administration (fasting state)

Perpetrator: grapefruit juice (food)

200 mL of normal-strength grapefruit juice three times a day for 3

days (8 am, 12 pm, and 8 pm).

PK measurements at 0-3h, 0-12h and 0-inf

PD measurements: platelet inhibition at 0-12 hours

Clin Pharmacol Ther. 2014 Mar;95(3):307-13.

Grapefruit juice-clopidogrel interactionimpact on pharmacokinetics

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clopidogrel active cis-metabolite (R-130964)

85% decrease in AUC0-3h

83.8% decrease in AUC0-inf

88.6% decrease in AUC ratio m/p

tmax and t 1/2 unaffected

No significant effect on clopidogrel

16.7% increase in AUC0-inf

Clin Pharmacol Ther. 2014 Mar;95(3):307-13

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Grapefruit juice-clopidogrel interactionimpact on pharmacodynamics (n=2)

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Average inhibition of P2Y12-mediated platelet aggregation:

- subject 1 (EM): decrease from 90% (with water) to 20% (with GFJ)

- subject 2 (PM): decrease from 47% (with water) to 12% (with GFJ)

Subject 2: CYP2C19*2/*2

Subject 1: CYP2C19*1/*1

WATER

Subject 1: CYP2C19*1/*1

Subject 2: CYP2C19*2/*2GFJ

Clin Pharmacol Ther. 2014 Mar;95(3):307-13

Authors’ conclusion

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�New type of grapefruit juice–drug interaction:

grapefruit juice is able to impair the bioactivation of a

prodrug

� Possible mechanism proposed:

inhibition of both CYP3A4- and CYP2C19-mediated

metabolism of clopidogrel

� Recommendation: avoid the concomitant use of

clopidogrel and grapefruit juice

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Victim: clopidogrel

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Intestinal absorption of clopidogrel is limited by the intestinal efflux pump P-gp.

Clopidogrel undergoes an extensive and complex metabolism in the liver.

CYP2C19 (45%) CYP3A4 (40%), 2B6 (33%)

CYP1A2 (36%) CYP2C19 (21%), 2C9 (6.8%)

clopidogrel 2-oxo-clopidogrel active cis-metabolite

(prodrug) CYP2B6 (19%) (inactive) paraoxonase (R-130964)

carboxylesterases

(CES1>CES2>>BChE) CES1>CES2>>BChE CE1>CES2

clopidogrel 2-oxo-clopidogrel R-130964

carboxylic acid carboxylic acid carboxylic acid

(inactive) (inactive) (inactive)

(In vitro fractions metabolized) Expert Opin Pharmacother. 2012 Apr;13(5):663-83.

~15% is bioactivated in the liver

~85%

Clopidogrel in vivo metabolism(effect of CYP inhibitors and Pharmacogenetics)

Perpetrator/

Genetic

variant

Enzymes

investigated

%∆ AUC

Perpetrator dose

Effect of

platelet

inhibition

Referencesprodrug

active

metabolite

ketoconazole CYP3A4 (+++)

CYP2C9 (+)

- -27.8 400 mg q.d, 10 d Yes Farid, 2007

fluoxetine CYP2C19 (+++) - -20.8 20 mg q.d, 5 d Yes Delavenne, 2013

omeprazole CYP2C19 (++) -

-

20.9

-

-30.4

-46.2

-47.7

-23.2

80mg q.d, 9 d

80mg q.d, 14 d

80mg q.d, 10 d

20 mg q.d, 7d

Yes Frelinger, 2012

Andersson, 2014

Angiolillo, 2011

Funck-Brentano, 2013

*0/*0 CYP2C19 -29; 194 -72.2; -43 Not Applicable Yes Kim, 2014

Simon, 2011

*1/*3;

*2/*2; *2/*3

CYP2C9 - -42 Not Applicable Yes Brandt, 2007

grapefruit

juice

CYP3A4 (++)

CYP2C19 ?

16.7 -83.8 200 ml t.i.d, 3 d Yes Holmberg, 2014

26

+++: potent; ++: moderate; +: weak

The individual inhibition studies of CYP2C19 and CYP3A4, as well as genetic variation with null or

limited activity do not reach the extent of the DDI observed between GFJ and clopidogrel.

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Clopidogrel as a substrate of

transporters?

In vitro: limited transport data available in the

literature

In vivo: clopidogrel is a P-gp substrate. Aspirin induced

intestinal P-gp lowering the oral bioavailability of

clopidogrel (Oh et al, 2014)

Pharmacogenetics: subjects homozygous variant

ABCB1c.3435TT vs. 3435CC+CT

27

clopidogrel active metabolite

Max %∆ AUC -80 to -68 -72 to -76Taubert, 2006; Karazniewicz-Lada, 2015

Case study results: Prodrug clopidogrel Cmax

and AUC were unchanged by grapefruit juice

administration

Conclusion: intestinal inhibition of uptake

transporters (OATP1A2 and/or 2B1) and/or

activation/induction of efflux transporter P-gp

are two mechanisms not involved in this

interaction.

28

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Grapefruit juice as a perpetrator in vitro

29

IC50 (µM) - Data summarized from DIDB

ConstituentsContent in juice

CYP3A4 CYP2C19 CYP2C9 CYP1A2

Naringin115000-384000 ng/mL

178 (felodipine)

1349 (quinidine)59 (flurbiprofen)

Naringenin9800-80000 ng/mL

12-200 (depending on

substrate)

2 (MFC)

2.6-3.5

2.6 (MFC)

12 (diclofenac, flurbiprofen)83-96

GF-I-150-400 ng/mL

0.003-0.07 (nifedipine)

0.012-0.013 (omeprazole)0.46 0.350 0.5

GF-I-450-400 ng/mL

0.003-0.07 (nifedipine)

0.012-0.013 (omeprazole)0.142 0.70 2.5

GF-I-22000-10000 ng/mL

1; Ki: 2.24 (midazolam)

1.5-5.5 (nifedipine)0.2-0.3 0.3-0.4 0.3-0.5

DHB2000-10000 ng/mL

15; Ki: 0.5-0.9 (midazolam)

0.65 (nifedipine)0.097-3 1-4 0.6-10

GF-I-5 0.670 (testosterone)

GF-I-6 0.620 (testosterone)

GF-I-1 and GF-I-4: furanocoumarin dimer; GF-I-2: bergamottin; DHB: 67-dihydroxybergamottin; GF-I-5: (R)-bergamottin-67-epoxide;

Furanocoumarins are potent inhibitors of CYP3A4, CYP2C19, CYP2C9 and CYP1A2 enzymes,

all involved to some extent in the bioactivation of clopidogrel.

Grapefruit juice as a perpetrator in vivo

30

Effect of GFJ on CYP probe disposition (Data summarized from DIDB)

Enzyme Probes GFJ dose ↑ %∆ AUC

CYP3A4 midazolam (oral)

midazolam (IV)

240 mL regular-S QD, 4 days

240 mL double-S QD, 3days

250 mL regular-S, twice

139.1

495

8.4 (no inhibition)

CYP2C19 lansoprazole 200 mL SD 20.9

CYP1A2 caffeine 300 mL, 1.5 days 32.7

CYP2C9

(others)

warfarin* 1 grapefruit each morning, 1 week INR of 4.77

1.5 L of GFJ per day, 10 days INR of 6.29

GFJ is a moderate-to-potent intestinal CYP3A inhibitor

GFJ weakly inhibits CYP2C19 (and maybe CYP1A2)Effect of GFJ on CYP2B6 and CYP2C9 probes were not evaluated in vivo.

*Bodiford, 2013: “Elevated international normalized ratio with the consumption of grapefruit and use of warfarin”

*Am J Health Syst Pharm.1999 Apr 1;56(7):676.

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Grapefruit juice as a perpetrator:transporter data

31

In vitro: IC50 (µM) - Data summarized from DIDB

R> 1.25: FDA cut-off for potential in vivo DDI

In vivo: GFJ has no significant effect on digoxin disposition(Clin Pharmacol Ther. 2001 Oct;70(4):311-6; Pharmacotherapy. 2003 Aug;23(8):979-87)

GFJ

componentsOATP1A2

(int)

OATP2B1

(int)

P-gp

(int/hep)

BCRP

(int/hep)

OATP1B1

(hep)

OATP1B3

(hep)

MATE1

(ren/hep)

Naringin3.6-75.5

4.63

I1/IC50: 350

2409

I1/IC50: 0.62- - 197.5 -

Naringenin

34349.2

I1/IC50 < 10-3

236

I1/IC50 < 10-237

101.1

I1/IC50:

0.073

81.6

I1/IC50:

0.090

-

GF-I-2- 60% at 10 µM -

3.19

I1/IC50: 7.75- -

39.8

I1/KI < 0.1

DHB- -

5.2

I2/IC50: 17.1

34

I1/IC50: 1.54- - -

IC50 Cmax/IC50 R

OATP1B1 101.1 µM 0.073 1.08

OATP1B3 81.6 µM 0.090 1.10

Limited evidence for the potential

inhibition of hepatic uptake of

clopidogrel preventing its bioactivation. (K. Mandery et al. European Journal of Pharmaceutical

Sciences 46 (2012) 79–85)

I1= Cmax I2= dose (mol)/250mL

Grapefruit juice as perpetrator

32

Evidence:

• GFJ affects CYP3A4 substrates undergoing extensive first-

pass metabolism

• Effect on P-gp appears to be minimal

Possible other mechanisms:

• Inhibition of CYP3A4, 2C19, and 1A2: does not explain

the dramatic decrease in exposure of clopidogrel active

metabolite

• Inhibition of hepatic OATP1B1 and OATP1B3 and possibly

other hepatic transporters: no strong evidence

supporting this hypothesisDrug Metab Dispos. 1997 Nov;25(11):1228-33. J Clin Invest. 1997 May 15;99(10):2545-53.

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GFJ-clopidogrel DDI – loss of efficacy(not published – presented in clinicaltrials.gov - 2011)

33

Effect of grapefruit juice (two small cans [11 oz total] of regular

strength GFJ in the morning) on platelet-inhibitory effect of

clopidogrel.

Clopidogrel dosage

regimen

% Platelet Inhibition (measured by Verify Now)

without GFJ with GFJ

300 mg single dose

loading dose (n=15)

41.2 (19.1) 23.4 (14.2)

∆: -43.2%

75 mg for 7 days

maintenance dose (n=17)

59 (22.5) 24.6 (24.2)

∆: -58.3%

GFJ decreases the efficacy of clopidogrel on

platelet inhibition

No statistical analysis provided for % platelet inhibition

clinicaltrials.gov, identifier: NCT00817999

Conclusion

34

• First case of non-intestinal GJF-drug interaction

• Mechanism not fully elucidated but potentially

involving inhibition of multiple enzymes including

CYP3A4 and CYP2C19 as well as hepatic

transporters

• Avoid drinking GFJ during clopidogrel chronic

treatment

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Acknowledgments

• Dr. Isabelle RAGUENEAU-MAJLESSI

• Dr. Jingjing YU

• Dr. Tasha RITCHIE

• Dr. Cathy YEUNG

• Dr. Katie OWENS

• Dr. Zhu ZHOU

• Dr. Jessica SONTHEIMER

• Dr. Nina ISOHERRANEN

• Marjorie IMPERIAL

• Grace LEE

• Chris KINSELLA35

Thank you!

36

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Additional slides

37

Naringenin and Hepatic OATPs

• Cmax – 2.010 µg/mL = 7.38 µM, with 135 mg dose (approx 241 mg naringenin/L grapefruit juice, so ~560 mL of grapefruit juice)

• Iin,max – 40.4 µM (calculated by authors)

• R = 1 + (fu * Iin,max)/IC50, assuming fu = 0.2 (moderately protein bound)

If R ≤ 1.1: clinical significance is very unlikely.

IC50 Cmax/IC50 R

OATP1B1 101.1 µM 0.073 1.08

OATP1B3 81.6 µM 0.090 1.10

K. Mandery et al. European Journal of Pharmaceutical Sciences 46 (2012) 79–8538

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Clopidogrel as a victim

39

� Marketed in 1997

� Irreversible P2Y12 platelet

inhibitor

� Indications: acute coronary

syndrome, recent MI, recent

stroke, or established peripheral

arterial disease

� Extensively metabolized: no

unchanged clopidogrel in urine

Drug Metab Rev. 2009;41(2):89-295

Grapefruit juice as precipitant

40

• Naringin

typical and abundant ingredient in GFJ: 115000 – 384000 ng/mL

(hand squeezed)

• Naringenin

aglycone of naringenin: 9800 – 80000 ng/mL (hand squeezed)

• Furanocoumarins (psoralens/bergaptens)

Bergamottin (GF-I-2)

(R)- 6’,7’-dihydrobergamottin (DHB)

(R)-bergamottin-6’,7’-epoxide (GF-I-5)

Paradisin A (GF-I-1)

Paradisin B (GF-I-4)

Paradisin C (GF-I-6)

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Grapefruit juice as precipitant

41

Grapefruit juices Naringin (mg/L) Naringenin bergaptens

Fresh (squeezed) 219 – 656 9.8 – 80 1.4 – 25

Fresh (by blender) 2713 – 4086 32 – 176 3 – 13

McCOY® 607 – 730 22 – 88 0.59 – 1.3

Sun Valley® 105 – 1197 24 – 162 3.4 – 6.7

Ocean Spray® (pink) 187 – 283 12 – 19 ND

Ocean Spray® (ruby red) 48 – 138 4.2 – 8.7 ND

Keri® 221 – 803 33 – 77 0.5 – 1.5

Robinson Brothers® 387 – 705 26 – 41 ND

Dew Drop® 386 – 612 32 – 48 1.0 – 1.3

Comparison of naringin, naringenin and bergapten contents in different brands of

fresh grapefruits.

Pharm Acta Hely. 2000 Apr;74(4):379-85 (PMID 10812937)