Food and Drug Interactions

Sloan-Kettering Institute

Mark G. Klang, PhD (cand), RPh, BCNSP

Research Pharmacy Supervisor

Overview

• Drug issues– ADME

• Administration issues– Drugs through

feeding tubes– Compatibility of

injectable drugs

• Stability of ingredients

• Vitamin stability• Contaminants

Drug Issues

• ADME – Absorption

• Involves how the drug dissolves and is released in GI

– Distribution – Involves drug moving in blood stream

– Metabolism – clearance of the drug by enzymes

– Excretion – liver or kidney removal

Absorbtion• Swallowing• Disintegration

– tablet swells– breaks up

• Dissolution– reactions with acid – faster when ionized

• Absorption– most post pyloric– in basic environment– require non-ionized state

Tablet breakup

Kinetic changes Liquid vs Tablet Kinetic changes Liquid vs Tablet

• Liquids absorbed faster• Onset faster• Extent of absorption

may be greater• In stomach liquids

expose drug to greater acidic degradation

Food Interactions with Absorption

• Milk products alter pH

• Metals chelate some medications

• Some foods compete for same absorption sites

• Food speeds GI speed – reduced absorption

• Degree of significance is important

Metabolism – Interaction with food

• Cytochrome P-450 in GI, liver Grapefruit juice made from frozen concentrate will alter this enzyme

• Many drugs for AIDS, HTN

• Effects occur 24 hours after ingestion

Excretion

• Urine acidity will change drug excretion

• Cranberry juice will alter pH and cause higher dissolution. This occurs with sulfonamides

• Lime juice is most acidic

Drug Administration through Feeding tubes• Most drug

products are not designed, tested, labeled nor approved for administration via feeding tube (FT)

• 13 listing in PDR

Clogging tubes

• Lumen size / circumference (French size)

• Length – longer loops

• No residual volume in jejunum. Tubing must be flushed. Clogging is usually due to undissolved drugs

PEG and PEJPEG and PEJ

Issues with Route of AdministrationIssues with Route of Administration

Physical Issues Drug Stability with Enteral FormulaPhysical Issues Drug Stability with Enteral Formula

• Admixture may result in reduced drug stability

• Examples:– Ciprofloxacin, Ofloxacin and Levofloxacin

was tested with electrolytes and Ensure

–Significant loss of drugs in Ensure

Median % Drug Lost in Ensure compared with H2O Median % Drug Lost in Ensure compared with H2O

82.5

45.8

61.3

0

10

20

30

40

50

60

70

80

90

Ciprofloxacin Ofloxacin Levofloxacin

% Lost

Cipro Study

• Prepared 3 concentrations in SGF

• 5, 2.5 and 1.25 mg/ml

• Higher dilution yielded highest dissolution and yield of the drug

• 5 mg/ml had decreased release compared to control

• Shouqian Shi and Oscar Camilo

Osmotic Issues

• Common Side Effects associated with Enteral Nutrition – 40% of TF diarrhea caused by excipients

Diarrhea, nausea, vomiting, cramping, distention & bloating

• Is it caused by:– The Enteral Nutrition ??– The Drug Therapy ??– Both ??

ticky - it’s a sugar

smolarity - causes diarrhea

eproducible - NOT, content changes often

loated feeling - causes gas

gnites - Cauterized diabetic bowels

heophylline - has most sorbitol

bscure - amount not on label

iquids- present in most liquid medications

U.S.P. Drug Problem Product ReportStools & Drug Doses per Hospital Day

0

2

4

6

8

10

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Hospital Day

# Stools # Diphenoxylate # Loperamide

Intravenous Nutrition Compatibility• Contain many ingredients

– Amino acids, dextrose, lipids, electrolytes, vitamins and trace elements

• Issues of compatibility can be significant. Precipitates can occur.

• Many patients receive medications simultaneously.

Lipid Compatibility

• Many institutions mix lipid in same container with other ingredients

• Lipid is an oil–in–water emulsion

• Electrolytes destabilize the emulsion

• Fat droplets aggregate• Clog blood vessels –

form emboli

Lipid Emulsion Research

• Lipids form larger droplets – but the average size remains the same.

• Repellent forces between droplets are neutralized – but zeta potential does not change

• Found accumulation in lungs of rats

• Filtering particles made droplets larger

Interface Interactions

(-)

(-)

(-)Ca

++

(-)

(-)(-)

(-)(-)

zeta potential

AA

AA

oil

interface

Sample B vs Filtered B

-5000

0

5000

10000

15000

20000

25000

30000

35000

1 2 2 3 5 7

11 16

23

33

48

71

10

3

15

0

22

0

32

0

46

7

Particle Size nm

Filtereed

TNA B

Filtering TNA

1.2 Micron (+) Filter

LipidDroplet

Ink bottle Effect

Intravenous Compatibility

• pH - acid base interactions

• Concentration - Vancomycin and ceftazidime.

• Crystal formation – Ascorbic Acid

• Precipitate formation – Ca + PO4

Phenytoin compatibility with enteral nutrition• Neurology patients

get this drug through feeding tube.

• When given with nutrition – levels drop

• Recommendations to hold feeding 2 hours before and after and increase dose

Phenytoin

• Controlled studies do not find interaction

• Only occurs in case reports

• In-vitro studies document the occurrence – but fail to show mechanism

Phenytoin

• Suspension formulation is very thick

• Adheres to surfaces – increases dosing errors

• Diluting drug improves dissolution

Phenytoin Dissolution

-20

-15

-10

-5

0

5

10

15

20

Water Osmolite CaCasein water Osmolite CaCasein

Suspension Tablet

25

12.5

6.25

Warfarin

• Anticoagulant used to reduce strokes• Inactivated by Vitamin K - broccoli• Enteral nutrition products contain Vitamin

K.• Warfarin activity drops when nutrition

given• Study shows warfarin binds to protein at

pH 8

Warfarin Binding

• pH 8 is not physiological

• This drug binds to plastic

• It adheres to feeding tube

• It binds to protein once absorbed, but not in the stomach at pH 1.2

Warfarin Binding

Warfarin recovery when mixed with chopped feeding tubes in water

0

0.5

1

1.5

5mg 5 mg /FT 10mg/FT 15 mg/FT add 2X FT

Emend (aprepant)

• Anti-nausea drug• Available in capsule

which can be opened.• Can this be given

through feeding tube?• The drug is insoluble in

water• Studying

Vitamin C – Ascorbic Acid

• High doses advised for flu and ills• Limited absorption dependent on

concentration.– More ingested = lower percent absorbed

• Higher levels produce faster excretion• High excretion will continue after high

doses stopped

Tigacycline

• Structurally similar to tetracycline

• Tetracycline is inactivated by metal

• Is tigalcycline affected?

• Being studied now

Aluminum

• Found in many drugs as a contaminant

• Evaluating impact on stability

• FDA attempting to legislate changes in amount

• Causes bone loss, Alzheimer's?– Linked to calcium

injection

MAOI

• Sensitivity to tyramine – causes hypertension

• Some antidepressants (new patch), antibiotics, chemotherapy

• Found in NYS extra-sharp cheddar cheese, Chianti and beer

Steroids – Nutrition issues

• Patient education essential

• Increased loss of electrolytes (K) retention of Na.

• Increased glucose level

• GI irritation

• Slowly taper off

Summary

• Everything interacts

• Food shares same ADME as do drugs

• Question all conclusive studies

• When in doubt, do more research