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