DOES GRAPEFRUIT JUICE ENHANCEDOES GRAPEFRUIT JUICE ENHANCE

THE CLINICAL EFFECTS OF ORALTHE CLINICAL EFFECTS OF ORAL

MORPHINE?MORPHINE?

Rodney Rodney McKeeverMcKeever, M.D., M.D.

T32-Clinical Pharmacology FellowT32-Clinical Pharmacology Fellow

INTRODUCTIONINTRODUCTION

Providing drug-food interaction (FDI) informationProviding drug-food interaction (FDI) information

to patients and caregivers is recognized as ato patients and caregivers is recognized as a

community practice standard, and required bycommunity practice standard, and required by

JCAHO (Joint Commission on Accreditation ofJCAHO (Joint Commission on Accreditation of

Healthcare Organizations).Healthcare Organizations).

Consumers have become more involved inConsumers have become more involved in

managing their own healthcaremanaging their own healthcare

Physicians need to monitor use of food products,Physicians need to monitor use of food products,

because of possibility of adverse reactions frombecause of possibility of adverse reactions from

drug interactionsdrug interactions

Overview : FDI

Lack of clinical data (controlled studiesLack of clinical data (controlled studies

or investigation)or investigation)

FDI Difficult to predictFDI Difficult to predict

Cannot assume no interactionCannot assume no interaction

Cannot simply ignore patient useCannot simply ignore patient use

Cannot blindly recommend against generalCannot blindly recommend against general

useuse

Cannot ignore potential benefits or Cannot ignore potential benefits or AEsAEs

High-carbohydrate meals decrease drug absorption*When the increased or decreased absorption effects of food are undesirable, take drug on an empty

stomach, either one hour before or two hours after meals.

Iron, levodopa, penicillins (most), tetracycline,

erythromycin

Acidic foods/juices and sodas (e.g., cola) significantly increase drug absorption

Ketoconazole

Decreased/delayed drug absorption

Famotidine

Food, especially high-fat meals, improves drug absorption; take with food, or within two hours of a

meal

Saquinavir, griseofulvin, itraconazole, lovastatin,

spironolactone

Food in general and acidic foods/juices significantly decrease drug absorptionDidanosine or ddI

Avoid taking with antacids (esp. magnesium and aluminum types) and iron products; significantly

decreased drug absorption

Fluoroquinolones (ciprofloxacin, levofloxacin, ofloxacin,

trovafloxacin), Tetracycline

Significant decrease in serum drug levelsACE inhibitors (captopril and moexipril)

Decreased/delayed drug absorptionAcetaminophen, aspirin, digoxin

Effect(s) of Food*Drugs

Table 3

Effects of Food on Drugs

Background and SignificanceBackground and Significance

There may be instances where interactions between aThere may be instances where interactions between adrug and food substances taken together might have thedrug and food substances taken together might have theadvantage of either to increase the bio-availability of theadvantage of either to increase the bio-availability of thedrug or to reduce the required dosage and still get thedrug or to reduce the required dosage and still get thehigher desired serum concentration of the drug.higher desired serum concentration of the drug.

Grapefruit has been receiving considerable attentionGrapefruit has been receiving considerable attentionlately for its interaction with many commonly prescribedlately for its interaction with many commonly prescribeddrugs.drugs.

GFJ inhibits the activity of the GFJ inhibits the activity of the cytochromecytochrome P450 P450isoenzymeisoenzyme CYP3A4, which is involved in the metabolism CYP3A4, which is involved in the metabolismof about half of all drugs prescribed (Medical Letter 2003;of about half of all drugs prescribed (Medical Letter 2003;45:46)45:46)

Foods That Affect Foods That Affect CytochromeCytochrome

P450P450 BroccoliBroccoli

CabbageCabbage

Other Cruciferous VegetablesOther Cruciferous Vegetables

SpinachSpinach

LeeksLeeks

OnionOnion

GarlicGarlic

ParsleyParsley

GrapefruitGrapefruit

Fried and charcoal broiled foodsFried and charcoal broiled foods

Smoked fish or meatSmoked fish or meat

HamHam

SausageSausage

Overview :Overview :

At LEAST 50 (57) At LEAST 50 (57) isoenzymesisoenzymes, grouped, grouped

based on their amino acid sequencesbased on their amino acid sequences

Example: CYP3A4: Example: CYP3A4: CytochromeCytochrome P450, P450,

family family ““33””, subfamily , subfamily ““AA”” and the 4 and the 4thth enzyme in enzyme in

the subfamilythe subfamily

Most CYP-450 enzymes involved in drugMost CYP-450 enzymes involved in drug

metabolism belong to the three distinctmetabolism belong to the three distinct

families, CYP1, CYP2 and CYP3 (50% of allfamilies, CYP1, CYP2 and CYP3 (50% of all

drugs)drugs)

Some drugs processed by several CYP450 Some drugs processed by several CYP450 isoenzymesisoenzymes

CytochromeCytochrome P450 P450

Cytochrome P450 NamingCytochrome P450 Naming

classification: CYP 3 A 4

family

>40% sequence-

homology sub-family

>55% sequence-

homology

isoenzyme

*15 A-B

allele

J R Oesterheld : Drug-Drug Interactions

ISOENZMYES OF CYTOCHROME P450 ISOENZMYES OF CYTOCHROME P450

CYP1A1

CYP1A2

CYP2A6

CYP2B_

CYP2C9

CYP2C19

CYP2D6

CYP2AE1

CYP3A4

CYP3A5

CYP3A7

CYP4A_

Shimada T et al. J Pharmacol Exp Ther 1994;270(1):414.

CYP3A

CYP2D6

CYP2C

CYP1A2CYP2E1

Relative Importance of

P450s in Drug Metabolism

CYP3A

CYP2C

CYP1A2

CYP2E1

?

CYP2D6

Relative Quantities

of P450s in Liver

CYP450CYP450

CYP1A1 Multiple PAH

CYP2A6 Liver aflatoxins

CYP2B6 Liver nicotine

CYP2C8 Liver taxol

CYP2E1 Liver, GI tract ethanol, benzene

CYP3A4 Liver, small intest. paracetamol

Isoenzyme Organ Typical substrate

Cytochrome P450Cytochrome P450

SummarySummary

CYP3A4 CYP3A4

CYP3A4 is responsible for metabolism of 60%CYP3A4 is responsible for metabolism of 60%

of all drugsof all drugs

It comprises approximately 28% of hepaticIt comprises approximately 28% of hepatic

cytochromecytochrome P450 P450

Ingestion of grapefruit juice reduces expressionIngestion of grapefruit juice reduces expression

of this enzymeof this enzyme

Inhibited by some regularly used drugsInhibited by some regularly used drugs

Grapefruit Juice-Drug Interactions

Time

Dru

g B

lood

Con

cen

trati

on

(A

UC

)

Drug Taken with GJ

Drug Taken without GJ

Grapefruit Juice Increases Grapefruit Juice Increases FelodipineFelodipine Oral Availability in Oral Availability in

Humans by Decreasing Intestinal CYP3A Protein ExpressionHumans by Decreasing Intestinal CYP3A Protein Expression

J.Clin. Invest. 99:10, p.2545-53, 1997

Hours

Dresser GK et al Clin Pharmacol Ther 2000;68(1):28–34

Hours after Dose Hours after Dose

P. B. Watkins 2003

Grapefruit Furanocoumarins

O O O

O

OH

OH

6',7', - 6',7', - DihydroxybergamottinDihydroxybergamottin

P. B. Watkins 2003

P. B. Watkins 2003

Morphine is a very common narcotic used for painMorphine is a very common narcotic used for pain

management; is considered the gold standard formanagement; is considered the gold standard for

analgesia and remains the most commonly used analgesia and remains the most commonly used opioidopioid

because of its relatively low cost and the availability ofbecause of its relatively low cost and the availability of

numerous dosage formsnumerous dosage forms

It is the naturally occurring alkaloid derived from the opium It is the naturally occurring alkaloid derived from the opium

poppy, poppy, PapaverPapaver somniferumsomniferum and is almost entirely metabolizedand is almost entirely metabolized

by the gut wall or the liver to a number of active or inactiveby the gut wall or the liver to a number of active or inactive

compounds.compounds.

Ninety percent of the dose is excreted within 24h. The principalNinety percent of the dose is excreted within 24h. The principal

route of metabolism is via phase-2 enzymes, e.g. UDP-route of metabolism is via phase-2 enzymes, e.g. UDP-

glucuronosylglucuronosyl transferasestransferases. Although . Although glucuronidationglucuronidation is generally is generally

regarded as the main pathway for morphine degradation, recentregarded as the main pathway for morphine degradation, recent

studies suggest that the N-studies suggest that the N-demethylationdemethylation by the by the cytochromecytochrome

P4503A4 (CYP3A) and CYP2C8 to P4503A4 (CYP3A) and CYP2C8 to normorphinenormorphine is also an is also an

important pathway [2, 3].important pathway [2, 3].

Background and SignificanceBackground and Significance

Chemically, morphine sulfate is 7,8-didehydro-4,5_-epoxy-17-methylmorphinan-

3,6_-diol sulfate (2:1) (salt) pentahydrate and has the following structural

formula:

(C17H19NO3)2•H2SO4____________Molecular Weight: 668.77

Morphine MetabolismMorphine Metabolism

A small amount of morphine undergoes N-demethylation

Morphine Morphine -6-glucuronide (active metabolite)/5-10%

Morphine Morphine -3-glucuronide (inactive metabolite)/75-85%

Morphine MetabolismMorphine Metabolism

Morphine -3-glucuronide is the major metabolite

Morphine has a relatively high hepatic extraction ratioMorphine has a relatively high hepatic extraction ratioand therefore its activity should not be affected byand therefore its activity should not be affected byenzyme induction however there have been reportsenzyme induction however there have been reportsconcerning possible interactions.concerning possible interactions.

It has been reported that morphine induced respiratoryIt has been reported that morphine induced respiratorydepression and the depression and the potentiationpotentiation of analgesia occurs by of analgesia occurs byenhancement of CYP3A4 inhibition by enhancement of CYP3A4 inhibition by cimetidinecimetidine [4, 5]. [4, 5].

Grapefruit juice is known also to inhibit the activity of theGrapefruit juice is known also to inhibit the activity of theCYP3A4 CYP3A4 isoenzymeisoenzyme ( (cytochromecytochrome P450 system), and can P450 system), and canpotentiatepotentiate the effects of drugs that are metabolized by the effects of drugs that are metabolized bythis mechanism [6].this mechanism [6].

RifampinRifampin-inducer of CYP3A4 decreases both morphine-inducer of CYP3A4 decreases both morphinelevels and its analgesic effect (levels and its analgesic effect (FrommFromm etaletal, , Pain Pain 1997)1997)

Background and SignificanceBackground and Significance

Uptake of orally administered drug proceeds after the stomach

passage via the small intestine.

In the gut and liver, a series of metabolic transformation occurs.

J R Oesterheld : Drug-Drug Interactions

Routes of Administration (summary)Routes of Administration (summary)

Only about 40% of the administered dose (MS) reaches the central compartment

because of pre-systemic elimination (i.e., metabolism in the gut wall and liver).

Copyright restrictions may apply.

Kotb, H. I. M. et al. Br. J. Anaesth. 2005 94:95-99; doi:10.1093/bja/aei007

Semi-log plot for serum concentration-time profile of morphine after oral administration of onetablet MST 30 mg to normal, primary and secondary liver cancer (data [SD])

Copyright restrictions may apply.

Kotb, H. I. M. et al. Br. J. Anaesth. 2005 94:95-99; doi:10.1093/bja/aei007

Serum concentration-time profile of morphine after single oral administration of MST 30 mgtablet to normal, primary and secondary liver cancer (data [SD])

Opioid equianalgesic dosage conversion

2-420NAOxycodone hydrochloride

2-43010Morphine sulfate

6-8105Methadone hydrochloride†

2-430075Meperidine hydrochloride

2-47.51.5Hydromorphone

hydrochloride

3-4200120Codeine phosphate or sulfate

Duration of action

(hr)*Oral (mg)Parenteral (mg)Drug

Several studies suggest that GFJ affectsSeveral studies suggest that GFJ affects

intestinal but not hepatic CYP3A4;but repeatedintestinal but not hepatic CYP3A4;but repeated

dosing (three times a day ) of large amountsdosing (three times a day ) of large amounts

(200-240ml, double strength) over several days(200-240ml, double strength) over several days

can inhibit hepatic CYP3A4 as well ( JJ can inhibit hepatic CYP3A4 as well ( JJ LijaLija etaletal,,

EurEur J J PharmacolPharmacol 2000; 56:411; ML 2000; 56:411; ML VeroneseVeronese

etaletal, J , J ClinClin PharmacolPharmacol 2003; 43:831) 2003; 43:831)

Morphine is metabolized by the gut wall inMorphine is metabolized by the gut wall in

addition to the liver, therefore its actions possiblyaddition to the liver, therefore its actions possibly

may be enhanced by the inhibitory effects ofmay be enhanced by the inhibitory effects of

grapefruit juice on the CYP3A metabolism.grapefruit juice on the CYP3A metabolism.

Background and SignificanceBackground and Significance

Grapefruit Juice Increases Grapefruit Juice Increases FelodipineFelodipine Oral Availability in Oral Availability in

Humans by Decreasing Intestinal CYP3A Protein ExpressionHumans by Decreasing Intestinal CYP3A Protein Expression

J.Clin. Invest. 99:10, p.2545-53, 1997

Hours

Purpose/AimPurpose/Aim

Compare the effects of consuming large quantities andCompare the effects of consuming large quantities and

more typical amounts of GFJ on the activity of hepaticmore typical amounts of GFJ on the activity of hepatic

and intestinal and intestinal cytochromecytochrome P450 3A4 in vivo; P450 3A4 in vivo;

correlate/measure morphine plasma levelscorrelate/measure morphine plasma levels

In general, the minimum effective analgesicIn general, the minimum effective analgesic

concentration in the plasma of non-tolerant patientsconcentration in the plasma of non-tolerant patients

ranges from approximately 5 to 20 ranges from approximately 5 to 20 ng/mLng/mL

Investigate if there is a possible interaction between GFJInvestigate if there is a possible interaction between GFJ

and Morphine, because to date there has been no suchand Morphine, because to date there has been no such

study, since it is felt to be metabolized principally bystudy, since it is felt to be metabolized principally by

glucuronidationglucuronidation

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3. Takeda S, etal. Modulation of UDP glucuronosyl transferase function by cytochrome P450.

Evidence for the alteration of UGT2B7-catalysed Glucuronidation of morphine by CYP3A4.

Molecular Pharmacology 2005; 67:665-72

4. Lam AM, Clement JL. Effect of cimetidine premedication on morphine-induced ventilatory

depression. Canadian Anaesthetists Society Journal 1984; 31:36-43.

5. Bluhm R, etal. Potentiation of opioid analgesia by H1 and H2 antagonists. Life Sciences

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101:729-37

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