C H A P T E R

44
DrugeNutrient Interactions in Renal Failure
Raimund Hirschberg
UCLA, Division of Nephrology and Hypertension, Harbor-UCLA Medical, Torrance, CA, USA

INTRODUCTION time [1]. In contrast, calcium channel blockers do not

appear to affect gastrointestinal motility [2]. Table 44.1
Foods and prescribed or over-the-counter medicines lists several drugs that may be prescribed to patients
can interact in multiple ways. Such interactions may with CKD and which may interfere with the gastric
result in reduced or increased drug effects or in (often emptying rate. Table 44.2 lists drugs that are absorbed
subtle) nutritional deficiencies. Drug efficacy may be more slowly when given concurrently with meals. To
reduced due to food-induced delayed or decreased optimize drug absorption, these medicines should be
absorption from the gastrointestinal tract. Diet or nutri- given one hour before or two hours after meals.
ents may induce or inhibit drug-metabolizing enzymes However, there are a few commonly administered
and increase or decrease the rate of metabolism of
a given drug. The rate of excretion of the drug or of
active or toxic metabolites may also be altered by dietary TABLE 44.1 Drugs Affecting the Gastric
effects. Emptying Rate (GER)1
The most commonly observed drugefood interaction
Increase GER Decrease GER
is altered drug absorption from the gastrointestinal tract,
Metoclopamide Anticholinergics
usually a decrease in the rate of absorption. Less
commonly, the drug absorption rate may be increased Reserpine Atropine
if taken concurrently with foods. Drugs can also induce Sodium bicarbonate Amitriptyline
certain specific nutrient deficiencies particularly for vita-
Ondensetron Imipramine
mins and minerals.
In patients with chronic kidney disease (CKD) or end- Analgesics
stage renal disease (ESRD), drugenutrient interactions Morphine
may lead to overt nutritional deficiencies particularly
Pentazocine
when the general nutritional status is poor or there are
specific, subclinical nutritional deficiencies. This chapter Isoniazid
will focus on interactions between drugs typically Chloroquine
prescribed to renal patients and foods.
Phenytoin

Aluminum hydroxide
Phenothiazines
EFFECT OF FOOD INTAKE ON DRUG
ABSORPTION Chlorpromazine
Diphenylhydramine
The intestinal absorption of many drugs is slowed
Promethazine
when administered concurrently with food, either
because of delayed gastric emptying or because of dilu- Sympathomimetics
tion of the drug in the intestinal contents. Some medica- Levodopa
tions, such as central a2-adrenergic drugs, can reduce
Amantadine
gastrointestinal motility and delay the emptying of
1
the stomach and, hence, increase oralefecal transit Adapted from [82,83].

Nutritional Management of Renal Disease 729 Copyright Ó 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-391934-2.00044-8
730 NUTRITIONAL MANAGEMENT OF RENAL DISEASE

TABLE 44.2 Drugs Undergoing Reduced or Delayed Absorption Dietary contents can also reduce gastrointestinal drug
if Administered with Food uptake by inhibiting organic acid transport proteins
(OATPs). Naringin and flavonoids in fruits, fruit juices
Acetaminophen Ferrous sulfate2 Nifedipine
and vegetables such as grapefruit and orange juice
Amoxicillin Fosinopril Norfloxacin have been shown to inhibit OATP1A2 [3]. The uptake
Ampicillin Furosemide Ofloxacin of drugs that are transported by this protein (fexofena-
dine, L-thyroxine, atenolol, ciprofloxacin) can be
Aspirin Glipizide Oxacillin
reduced by as much as 50% [3]. Etoposide absorption
3
Benazepril Hydralazine Oxytetracycline2 is also substantially reduced by grapefruit juice [4].
Captopril Ibuprofen Penicillamine Subclinical or overt iron deficiency is commonly
observed in patients with advanced CKD or end-stage
Cephalexin Indomethacin Pravastatin
renal disease. Low or empty iron stores may be caused
Cephaclor Isoniazid Ramipril by reduced nutrient and, hence, iron intakes as well as
Cimetidine 1
Ketoconazole Rifampin subtle iron losses. Iron deficiency is the most common
1 reason for resistance to erythropoietin in patients with
Ciprofloxacin Ketoprofen Simvastatin
renal failure. Experimental studies have shown that
Clindamycin Levodopa Spironolactone administration of the phosphate binder calcium
Demeclocycline Levothyroxine3 Sulindac carbonate (CaCO3) with foods reduces the bioavail-
ability of iron from oral iron sulfate [5]. Apparently, in
Digoxin Lisinopril Tacrolimus
the presence of calcium, iron is taken up normally into
Docycycline Methotrexate Tetracycline2 the gut mucosa, but the transfer through mucosal
Enalapril Misoprostol Zidovudine cytoplasm and/or basolateral membranes is reduced.
This interaction is bypassed by intravenous iron
Erythromycin Nicardipine Zink salts
administration.
1
Concurrent administration with caffeine-containing foods may increase caffeine uptake
2
Mainly dairy products
3
Particularly enteral formulas.

EFFECTS OF NUTRIENTS ON DRUG

oral medicines that will undergo more effective absorp- METABOLISM
tion when administered with foods (Table 44.3). In most
circumstances the food-dependent increase in drug Dietary Protein and Lipids
absorption may enhance drug efficacy. However,
serious toxic side effects may arise, such as when The hepatic clearance of some drugs is reduced in
lithium or cyclosporine is given with foods. renal failure [6]. Drugs that are metabolized by oxida-
tion, conjugation or both processes may be predisposed
to decreased hepatic clearance in CKD. High protein
TABLE 44.3 Drugs that are Absorbed More diets can raise the activity of drugs that are metabolized
Effectively If Given with Food through cytochrome P-450-dependent mixed function
oxidases [7]. High protein diets accelerate the metabolic
Buspirone Griseofulvin
clearance of some drugs such as theophylline and
Carbamazepine Isradipine propranolol by about 30 to 60% compared to low protein
Cefpodoxime Labetolol diets [8].
Low protein diets also reduce the activity of xanthine
Cefuroxime Lithium salts
oxidase [9] and increase the plasma levels of allopurinol
Chlorothiazide Metoprolol and oxipurinol. Since oxipurinol accounts for some of
Cyclosporine Morphine the adverse effects of allopurinol, the concurrent
prescription of low protein diets and allopurinol may
Diazepam Nitrofurantoin
increase the likelihood of allopurinol toxicity [9]. The
Dicumarol Propaphenone prescription of low protein diets to patients with CKD
Diltiazem Propranolol may reduce also the sulfate conjugation of some drugs,
although clinical studies directly examining this ques-
Etretinate Quinidine
tion in patients or normal subjects are lacking. Drug sul-
Famotidine Sertraline fation depends on the availability of sulfur-containing
Felodipine Triclopidine amino acids and the possible release of sulfur in the
gut by the action of intestinal sulfatases.
 DRUGeNUTRIENT INTERACTIONS IN RENAL FAILURE 731
Cruciferous Vegetables and Drug Metabolism TABLE 44.4 Effects of Vitamin and Trace Element Alterations
on Oxidative Drug Metabolism1
Drug metabolism can be affected by other compounds
derived from certain foods. For example, various indoles Vitamin A deficiency Y P-450
that originate from cruciferous vegetables such as Y Metabolism of aminopyrine,
cabbage and Brussels sprouts, enhance oxidation and Coumadin
increase the metabolic clearance rate of medicines. Vitamin A, high dose [ Metabolism of Coumadin
Such foods also may enhance drug glucuronidation in
healthy subjects, e.g., for acetaminophen [10]. Diet- Niacin deficiency Y Metabolism of anesthetics
derived compounds may affect the activity of the P-450 Riboflavin deficiency Y NADPH:P-450 reductase
enzyme species, and such substances can compete as [ Aminopyrine metabolism
substrates for the P-450-dependent monooxygenase
system [11]. Indole-3-carbinol and related compounds Vitamin C deficiency Y P-450
that are present in cruciferous vegetables, particularly Y NADPH:P-450 reductase
Brussels sprouts, are potent inducers of the intestinal Y Monooxigenase activities
P-450 IA1 (CYP1A1) and hepatic CYP1A1 and CYP1A2
isoenzymes [12]. Folic acid deficiency Y Induction of P-450IIB1 by
barbiturates
Aluminum, high dose Y Hepatic P-450
Nutrients and Cytochrome P-450-Dependent
Selenium deficiency Y Induction of P-450 by
Drug Metabolism phenobarbital
Increased dietary protein augments hepatic micro- Zinc deficiency Y Phenobarbital and aminopyrine
somal cytochrome P-450 content probably through tryp- metabolism
tophan and sulfur amino acids [13]. In contrast, the 1
Adapted from [11].
activity of this enzyme system is reduced by low protein,
high carbohydrate or fat diets, flavonoids (i.e., contained
in citrus fruits and some vegetables), large doses of ribo- normal subjects naringin inhibits the metabolism of the
flavin and possibly during total parenteral nutrition [12]. CYP3A4 substrate nisoldipine only moderately giving
The cytochrome P-450IIE1 (CYP2E1) isoenzyme is rise to the importance of other compounds in grapefruit
induced by dietary lipids [14]. This isoenzyme partici- juice as inhibitors of this cytochrome P-450 isoenzyme
pates in the metabolism of acetaminophen, enflurane [18]. Although the effect of these grapefruit juice
and halothane [11]. Moreover, the CYP2E1 isoenzyme compounds on CYP3A4 may be clinically more impor-
is also activated by fasting, as well as by thiamine defi- tant, they also tend to inhibit several other cytochrome
ciency [14]. Several other alterations in the micronutrient P-450 isoenzymes such as CYP1A2, CYP2C9, CYP2C19
status can affect the oxidative metabolism of drugs and CYP2D6 [16,17].
(Table 44.4). CYP3A4 is present in relatively large concentrations in
the wall of the small intestine where it contributes to the
Cytochrome P-450 Isoenzyme Activity first pass metabolism of several drugs limiting the
amount of active drug that reaches the blood stream.
and Citrus Juice Compounds
The inhibition of CYP3A4 by compounds in grapefruit
Flavonoids, such as naringin, are present in rather juice and other citrus fruit juices is clinically important
large amounts in citrus fruits, citrus juices and some since this isoenzyme plays a major role in the metabolism
vegetables. The related aglycone, naringenin, is readily of drugs that are commonly used in patients with CKD
formed in humans from its precursor. This compound, or end-stage renal disease. These include cyclosporine
like other flavonoids, inhibits the cytochrome P-450 A, the dihydropyridine calcium channel blockers
3A4 isoenzyme. Grapefruit juice which is perhaps the nifedipine, nimodipine, felodipine, nitrendipine and
food most potently inhibiting CYP3A4 contains naringe- nisoldipine; the calcium channel blocker verapamil;
nin but also psoralen derivatives which are also thought saquinavir; diazepam, midazolam, triazolam, terfena-
to inhibit this isoenzyme [15]. In-vitro studies identified dine and lovastatin [15,18,19]. The bioavailability of these
several other compounds that were extracted from drugs is increased by co-administration with grapefruit
grapefruit juice and inhibit CYP3A4 [16]. Many different juice and, perhaps, even more so in subjects consuming
flavonoids can severely inhibit CYP3A4 (as much as large amounts of citrus juices chronically. For example,
100% in-vitro). These compounds are also found in other ingestion of diazepam, 5 mg, with 250 mL of grapefruit
citrus juices and fruits, fennel, bell pepper, celery, carrots juice as compared to water increases the diazepam
as well as ginkgo biloba [17]. In clinical studies in area-under-the-curve 3.2-fold [20]. The drugenutrient
732 NUTRITIONAL MANAGEMENT OF RENAL DISEASE
interaction between compounds in citrus juices and
dihydropyridine calcium channel blockers has signifi-
cant clinical implications. First, the increased plasma
levels of the drugs may raise the incidence of adverse
effects. Second, in hypertensive patients treated with
dihydropyridines, sporadic concomitant ingestion of
grapefruit juice may cause symptomatic hypotension.
Third, the combination of a dihydropyridine antihyper-
tensive with grapefruit juice can increase the therapeutic
efficacy. This has been illustrated in a published case
report [21].
Large doses of vitamin C given as nutritional supple-
ments to patients without ascorbic acid deficiency may
increase the rate of oxidative drug metabolism [22].
High vitamin C intakes can also reduce the rate of
sulfate conjugation of drugs, such as acetaminophen,
by competing for the available sulfate. Dietary supple-
mentation with large doses of pyridoxine may increase
the metabolism and decrease the therapeutic efficacy
of levodopa, since this vitamin is a cofactor for the
dopa decarboxylase [23]. In contrast, St. John’s Wort
induces CYP3A4 and accelerates metabolism of some
drugs.
Nutrients and Urinary Excretion of Drugs
The deficiency in some trace elements such as iron,
zinc, copper, and selenium has been shown to influence
the mixed function oxidase system in experimental
animals, but for most such elements, studies in humans
are not available. Moreover, even marked iron defi-
ciency in man does not appear to affect oxidative drug
metabolism.
In CKD the half-life of drugs that are primarily
metabolized by hepatic glucuronidation may be pro-
longed [24,25]. There is circumstantial evidence that
renal insufficiency per-se reduces hepatic drug clearance
[26]. Although it is possible that fasting, malnutrition or
specific nutrient deficiencies may alter the hepatic glu-
curonidation of some drugs, the literature at present
does not provide clearly supportive data.
The urinary excretion of certain drugs or of bioactive
or toxic metabolites does not only depend on the degree
of renal failure, i.e. GFR or creatinine clearance, but also
on urinary pH [27]. In patients with normal renal func-
tion and even in patients with moderate or even
advanced CKD, urinary pH depends largely on dietary
intakes, at least during the post-absorptive period. A
low protein diet produces more alkaline urine, and
conversely, a high protein diet results in more acidic
urine. Drugs or drug metabolites that are weak bases
are more efficiently excreted in acidic urine, whereas
more alkaline urine will promote the excretion of drugs
or metabolites that are weak acids. Foods that poten-
tially acidify the urine include meats, fish, eggs, cheese,
bread, cranberries, plums and prunes. More alkaline
urine can be caused by milk, various fruits and all vege-
tables except corn and lentils [28].
INTERACTIONS OF FOOD
SUPPLEMENTS WITH DRUGS
Patients with advanced CKD and those on mainte-
nance dialysis are often prescribed food supplements,
such as vitamins and iron preparations, or phosphate
binders. Specific interactions between certain drugs
and these food supplements have been described that
may not only reduce the blood levels of the drug but
may reduce the drug efficacy. Thus, it may be necessary
to separate the timing of the intake of the food supple-
ment from that of the drug. In general, the drug should
be taken one hour before or two hours after the supple-
ment, but in some circumstances this period of time
should be even longer (up to 4 h).
Supplemental folic acid decreases the blood levels of
phenobarbital [29] and may lead to break-through
seizures. Pyridoxine (vitamin B6) when given in large
dosages (400 mg/day) can also reduce the serum levels
of phenobarbital, possibly by increasing the activity of
pyridoxal phosphate-dependent enzymes. In animal
experiments, large doses of pyridoxine may reduce the
activity of isonicotinic acid against tuberculosis. Pyri-
doxine appears to form a Schiff base with isonicotinic
acid which is then excreted in the urine or removed
during dialysis [30]. Concomitant therapy with pyri-
doxine and L-dopa in patients with Parkinson’s disease
reduces the efficacy of the latter drug and worsens the
disease symptoms.
Excess intake of vitamin E can induce a hemorrhagic
state in laboratory animals caused by vitamin K defi-
ciency [31]. Patients on Coumadin therapy are at risk
for developing hemorrhages that result from unwar-
ranted further suppression of the vitamin K-dependent
clotting factors by concomitant intake of vitamin E. It
has been suggested that megadoses of vitamin C
(>1 g/day) may lead to vitamin B12 deficiency appar-
ently by destruction of vitamin B12 by vitamin C when
they are taken together.
Clinically important interactions occur between iron
supplements or phosphate binders and fluoroquino-
lone antibiotics [32]. Bioavailability of ciprofloxacin is
reduced if the drug is co-administered with aluminum
hydroxide-containing phosphate binders. Magnesium
hydroxide as well as aluminum hydroxide reduce the
bioavailability of ciprofloxacin by as much as 90%
when given concomitantly or within <0.5 hours, and
a lesser but still significant reduction occurs when
the drug is given within up to 4 hours after the antacid
[33]. Similar reductions in the bioavailability occur for
 DRUGeNUTRIENT INTERACTIONS IN RENAL FAILURE
other fluoroquinolone antibiotics, such as norfloxacin,
ofloxacin and enoxacin when administered up to four
hours after intake of aluminum, magnesium or calcium
containing phosphate binders [34]. A significant
decrease in the bioavailability of fluoroquinolones
was also described by several authors to occur upon
co-administration with several oral iron supplement
preparations such as ferrous sulfate, fumarate or
gluconate. Calcium-containing phosphate binders or
antacids have also been shown to reduce the bioavail-
ability of tetracyclines [35]. Sevelamer does not appear
to have such effects on drug bioavailability. The reduc-
tion of iron absorption from diet or ferrous sulfate due
to co-administration of calcium-containing phosphate
binders has been discussed earlier in this chapter.
DRUG-INDUCED NUTRITIONAL
DEFICIENCIES
Several prescribed or over-the-counter medicines
reduce appetite and food intake. In patients with CKD
or on maintenance dialysis this may aggravate an
already poor nutritional status and may contribute to
frank malnutrition. However, of greater concern are
more specific interactions of prescribed drugs with
micronutrients, mainly with certain vitamins and
minerals.
Drug-Induced Vitamin Deficiencies
Vitamin metabolism and requirements in renal
disease and renal failure are described in Chapter
24. Thiamine deficiency may be aggravated or caused
by chronic alcoholism. The literature, at present, does
not suggest that specific short-term or long-term drug
therapies may cause vitamin B1 deficiency. However,
thiamine deficiency may occur in severely ill patients
who undergo parenteral nutrition [36,37]. Thiamine is
a co-enzyme for pyruvate dehydrogenase, and thia-
mine deficiency may cause the acute onset of unex-
plained, severe lactic acidosis [36e38]. Riboflavin
deficiency can be caused or aggravated by long-term
administration of chlorpromazine or amitriptyline.
Pyridoxine deficiency may be caused by long-term
treatment with isoniazid. It is recommended that
vitamin B6 supplements (10e15 mg/day) should be
prescribed for the entire period of time that isoniazid
is taken. Vitamin B6 deficiency may also be caused by
hydralazine and penicillamine [23]. High doses of
pyridoxine hydrochloride reduce the serum levels
of anticonvulsants and may reduce the clinical seizure
control. Chronic vitamin B12 deficiency may develop
during long-term treatment with colchicine or
cimetidine [39,40].
733
Several drugs antagonize folic acid and may cause
megaloblastic anemia. These include phenytoin, pheno-
barbital, sulphasalazine, triamterene, trimethoprim, tri-
metrexate and methotrexate [41e43]. On the other
hand, folate supplementation may interact with these
medicines and reduce their clinical efficacy. Daily
dosages of folate of more than 5 mg reduces the plasma
levels of phenytoin and phenobarbital and may reduce
their therapeutic efficacy [44]. A risk for the develop-
ment of niacin deficiency may exist when treatment
with isoniazid is prescribed. During such treatment,
concurrent administration of niacin (100 mg/day) may
be advisable. Retinoids and possibly retinol increase
the blood cyclosporine levels [45]. Vitamin A supple-
ments should be avoided in renal patients. In addition
to Coumadin anticoagulants, there are a number of
drugs that can cause vitamin K deficiency and that
may induce or enhance severe bleeding. This has been
described particularly with the administration of moxa-
lactam, cefotetan, cefamandole, cefoperazone and other
cephalosporins that contain the methylthiotetrazole side
chain. Vitamin K supplements should be administered
concurrently with these antibiotics [46,47]. Weaker
anti-vitamin K effects have been shown with tetracycline
and cholestyramine [48]. Ingestion of megadoses of
vitamin E can cause vitamin K deficiency and should
be avoided [31].
Drug-induced osteomalacia can be due to chronic
intake of anticonvulsants, isoniazid and possibly cimeti-
dine. Anticonvulsant therapy with phenytoin, phenobar-
bital, or carbamazepine results in reduced levels of 24,25-
dihydroxyvitamin D3, and this may play a role in the
anticonvulsant-induced osteomalacia [49]. In patients
with CKD this drug-induced risk for osteomalacia may
be additive to the increased risk of renal bone disease.
Patients undergoing chronic dialysis therapy are often
supplemented with 1,25-dihydroxycholecalciferol or
analogues. However, in patients with moderate CKD
not receiving 1,25-dihydroxycholecalciferol, vitamin D
supplements should be given concurrently with the
above drug treatments.
Drug-Induced Mineral and Trace Element
Deficiencies
As a rule, the intakes of many minerals such as Na, K,
Mg, Ca and P correlate with the intake of nitrogen [50].
Mineral and trace element deficiencies may develop due
to poor nutritional intakes and elderly patients are at
greater risk. Mineral depletion can occur due to poor
gastrointestinal absorption and/or enhanced renal
excretion, the latter mainly in patients with lesser
degrees of CKD. Both, reduced absorption and
enhanced excretion of minerals can be caused by drug
therapy. Potassium, calcium, magnesium, iron and zinc
734 NUTRITIONAL MANAGEMENT OF RENAL DISEASE
are the most common minerals that become depleted in
patients with CKD. Drug-induced potassium deficiency
in patients with chronic renal failure most commonly
results from diuretic therapy and can be caused by
both thiazide and loop diuretics. With diuretic therapy,
magnesium deficiency may also develop.
Concurrent intake of aminoglycosides and cephalo-
sporin antibiotics can be interactive and cause potas-
sium (and magnesium) depletion, particularly when
intakes of these minerals are low which may occur
with ingestion of low protein diets. Hypokalemia can
also occur with gentamycin toxicity and during treat-
ment with amphotericin B. Potassium deficiency may
also be caused by laxative abuse with resulting potas-
sium losses through the gastrointestinal tract. Lithium
carbonate and levodopa can contribute to potassium
deficiency [51]. Hypokalemia and potassium depletion
worsen blood pressure levels in hypertensive patients
and may contribute to the thiazide-induced carbohy-
drate intolerance [52].
Calcium deficiency can be caused by poor dietary
intake, primary malabsorption or vitamin D-deficiency-
induced malabsorption, or drug-induced hypercalciuria.
Primary calcium malabsorption can result from enterop-
athy caused by neomycin, colchicine, methotrexate and
corticosteroids [53]. Aluminum and magnesium
hydroxide may reduce calcium absorption. Phenytoin
and phenobarbital may interfere with vitamin D metabo-
lism as described above. Loop diuretics, such as furose-
mide and ethacrynic acid can cause hypocalcemia
secondary to hypercalciuria [54]. In patients with chronic
renal failure combined treatments with drugs that inter-
fere with calcium metabolism are not uncommon.
Hypercalcemia in patients with CKD may result in
soft tissue calcification and nephrocalcinosis that may
contribute to the progression of renal disease or may
itself cause CKD. The long-term combined intakes of
large amounts of calcium carbonate and (vitamin
D-fortified) milk can lead to severe chronic hypercal-
cemia and nephrocalcinosis causing CKD, the so-called
milk-alkali syndrome [55]. In CKD, hypercalcemia may
result from the intake of calcium-containing phosphate
binders and/or vitamin D derivatives.
Hyperoxalemia and hyperoxaluria can be caused or
aggravated by vitamin C supplementation, even at
moderate doses (i.e., 500 mg/day) [56]. Patients who
eat relatively large amounts of foods that generate
oxalate (e.g., green salads) and take moderate or mega-
doses of vitamin C have an increased risk to develop
hyperoxalemia-associated complications [56].
Zinc deficiency may be caused or worsened by total
parenteral nutrition without adequate zinc intake [57].
Administration of penicillamine or corticosteroids
have also been associated with zinc deficiency [58].
Zinc depletion causes or contributes to clinical
symptoms that are often observed in patients with
CKD, such as loss of appetite and altered taste and
smell sensation. Loss of taste or smell may lead to
reduced food intake and, hence, malnutrition. Aspirin
(even at the low dose of 81 mg/day), ibuprofen and
other non-steroidal anti-inflammatory drugs may
cause occult gastrointestinal bleeding and contribute
to iron losses [59]. Iron depletion and anemia may
also be caused by poor food intake or reduced
bioavailability from non-heme iron in foods such as
due to concomitant calcium-containing phosphate
binders. This has been discussed above. There are
not sufficient data to indicate whether there are impor-
tant drug interactions with other trace elements, such
as selenium, molybdenum, chromium, manganese,
rubidium and others.
TAURINE AND ACE-INHIBITOR
EFFECTS
The amino acid taurine blocks actions of angiotensin
II by inhibiting cellular Caþþ-uptake and angiotensin II
signaling [60]. In experimental in-vitro and in-vivo
studies taurine food supplements were found to have
renal antifibrogenic effects comparable to those of
ACE-inhibitors [61].
Serum and blood cell taurine levels tend to be lower
in diabetics compared to normal subjects and taurine
food supplements can normalize taurine levels [62].
Foods rich in taurine include seafood, particularly crus-
taceans and molluscs, and lesser amounts are present in
beef, pork and lamb [63]. Taurine containing food
supplements are available over the counter. Whether
increased dietary taurine will indeed reduce the
progression of renal disease and/or reduce the cardio-
vascular mortality in chronic dialysis patients is
unknown due to the lack of respective clinical trials.
Nevertheless, this may be an example of collaborative,
beneficial drugenutrient interaction.
NUTRIENT INTERACTIONS WITH
ORAL ANTICOAGULANTS
Until recently, Coumadin was the mainstay of oral
anticoagulation therapy in non-renal as well as CKD-
patients. This drug is a prime example of the importance
of foods that can interfere with drug actions. This is
mainly because of the small therapeutic window
between under- and overdose as well as its reduced effi-
cacy by dietary vitamin K intakes. Table 44.5 summarizes
commonly consumed foods with relatively high vitamin
K content. In contrast, the intake of large amounts of
vitamin E can cause vitamin K deficiency [31].
 DRUGeNUTRIENT INTERACTIONS IN RENAL FAILURE
TABLE 44.5 Commonly Consumed Foods High in Vitamin K
Content
Beef liver Cheese Lettuce
Broccoli Collard greens Spinach
Brussels sprouts Green tea Soybean
Cabbage Lentils Turnip greens
Several novel orally effective small molecule factor Xa
or thrombin enzyme inhibitor anticoagulants have
recently been approved by regulatory agencies (rivarox-
aban, dabigatran) or are in various stages of clinical and
registrative development in the US and Europe (apica-
ban, edoxaban, betrixaban). Rivaroxaban and dabiga-
tran are approved for patients with CKD stages 1-3B
but not or only with caution in CKD 4 and 5. High fat,
high calorie diets tend to reduce the rate of absorption
of dabigatran but overall drug availability is not
substantially different from fasting [64]. Similar food
interactions were shown for rivaroxaban [65]. Other
important food interactions have not yet emerged. Since
these drugs are in clinical use for only a short period of
time, other drug nutrient interactions may come to
attention.
Apixaban, edoxaban and rivaroxaban are mainly
metabolized through CYP3A4. Thus, nutrients and
food supplements that induce CYP3A4 such as St. John’s
Wort might reduce drug levels and anticoagulant effi-
cacy. Over-anticoagulation could occur with large
amounts of citrus juice intake due to CYP3A4 inhibition.
Thus far, this has not materialized. Betrixaban and dabi-
gatran are not metabolized by CYP450 enzymes.
INTERACTIONS OF CALCINEURIN
INHIBITORS WITH NUTRIENTS
735
caused by metabolism in the small bowel wall [68].
Cyclosporine is metabolized by oxidation in liver micro-
somes through the cytochrome P-450 3A isoenzyme
system [69]. This enzyme system is also expressed in
the small bowel wall which explains the first-pass
metabolism of cyclosporine A [70].
Cyclosporine A is a highly lipid-soluble drug, and
about 40% of cyclosporine in plasma is bound to lipo-
proteins. Thus, it is reasonable to speculate that dietary
fat intakes or the fat content of meals may raise the
gastrointestinal absorption and plasma levels of cyclo-
sporine A but this has not been confirmed in clinical
trials.
As indicated above, citrus juices, particularly grape-
fruit juice, reduce the metabolic rate of Cyclosporine
and raise its blood levels [71], possibly through the
inhibitory effects of flavonoids and other compounds
on cytochrome P-450 3A enzymes [15]. The inhibition
of CYP3A4 by grapefruit juice and other citrus juices
and fruits raises the area-under-the-curve and causes
an increase in the 24 hr trough cyclosporine level [72].
St. John’s Wort and caspofungin induces CYP3A4
activity. Other drugs that inhibit or reduce cyclosporine
A levels due to effects on CYP3A are listed in Tables 44.6
and 44.7.
Both cyclosporine and tacrolimus can cause a number
of metabolic complications including phosphorous,
TABLE 44.6 Drugs that Increase Blood Cyclo-
sporine A Levels Due to Inhibition
of or Competition with CYP3A
Isoenzymes1
Ceftazidime Ketoconazole
Cimetidine Nicardipine
Diltiazem Norfloxacin
Erythromycin Omeprazole
Fluconazole Ponsinomycin

Treatments with cyclosporine A or tacrolimus Imipenem Ranitidine

continue to be part of many immunosuppressive regi- Itraconazole Verapamil
mens that are used in kidney transplantation. Cyclo- 1
Adapted from [66,84].
sporine has several side effects which include
nephrotoxicity, hepatotoxicity, hypertrichosis, gingival
hyperplasia and hyperuricemia and gout (7% of TABLE 44.7 Drugs that Decrease Blood Cyclo-
patients), the latter particularly when used together sporine A Levels Due to Induction
with loop diuretics [66]. Cyclosporine is incompletely of CYP3A Isoenzymes1
absorbed from the gastrointestinal tract and administra- Barbiturates Nafcillin
tion of the drug with foods tends to increase absorption.
Benzodiazepines Phenytoin
Oral administration of cyclosporine A together with
food and bile salts increases the bioavailability of the Carbamazepin Rifampicin
drug apparently due to improved absorption. However, Cephalosporins Trimethoprim
co-administration of cyclosporine with bile salts alone
Isoniazid Valproic acid
does not raise the cyclosporine blood levels [67]. The
1
incomplete absorption of intact cyclosporine is, in part, Adapted from [66].
736 NUTRITIONAL MANAGEMENT OF RENAL DISEASE
magnesium or potassium depletion, hyperkalemia,
glucose intolerance and diabetes mellitus and hyperli-
poproteinemia. Tacrolimus is mainly metabolized
through CYP3A enzymes. Hence, food/food supple-
ment interactions can affect tacrolimus blood levels: St.
John’s Wort (as well as caspofungin) induces CYP3A
and may decrease tacrolimus blood levels. Grapefruit
juice which blocks this enzyme system increases blood
levels. Drug inhibitors of CYP3A (calcium channel
blockers and azoles) can increase tacrolimus levels.
Absorption of tacrolimus from the gastrointestinal
tract is substantially influenced by food: Absorption is
greatest with fasting. High fat diets reduce tacrolimus
absorption and drug availability more than high carbo-
hydrate diets [73].
ENTERAL TUBE FEEDING AND ORAL
DRUG ADMINISTRATION
Enteral tube feeding may be a necessary or desirable
mode of nutrient delivery in some patients with CKD or
ESRD either transiently during periods of acute, severe
illness or for longer periods of time. In such patients,
drugs may be administered preferably by intravenous
routes, but enteral drug administration sometimes may
be necessary, since many medicine preparations are
not available for intravenous infusion.
Several considerations should be taken into account
when giving oral drug preparations through enteral
feeding tubes. First, oral medicines should be delivered
into the stomach to ensure proper preparation for subse-
quent drug absorption in the jejunum. Second, drugs
should be used in liquid form rather than as crushed
tablets. Third, slow-release or enteric-coated tablets
should not be crushed at all. Fourth, drugs may not be
compatible with the tube feeding formula and should
not be mixed with formula. Thus, tubes should be
flushed with water before and after drug administration.
Fifth, the osmolality of some liquid drug preparations
may be very high and may add to the osmolality of
the formula. A complete list of commercially available
liquid preparations of commonly used drugs has been
published elsewhere [74,75].
Only few studies have examined the bioavailability of
drugs when administered with enteral formulas, and
this information is not available for most medicines.
Phenytoin bioavailability, for example, is much reduced
when given with enteral formulas as compared to
a similar dose given orally [76,77]. Effervescent potas-
sium tablet preparations causes marked coagulation of
the enteral formula, whereas potassium chloride or
gluconate solutions are compatible [78]. Administration
of aluminum-containing phosphate binders with some
enteral formulas can lead to precipitation of formula
proteins with the aluminum salts and gastrointestinal
plug formation can occur [79]. Case reports have sug-
gested that enteral tube feeding causes resistance to
warfarin [79,80]. Apparently, this results from the antag-
onistic effect of vitamin K that is present in enteral
formulas [74]. In patients undergoing treatment with
warfarin, a formula with a lesser vitamin K content
should be used and will improve the response to
warfarin. There is also evidence that warfarin may
directly bind to the feeding tube reducing drug avail-
ability [81]. Some drug compounds are light sensitive
and inactivated by light exposure and preparation and
tube administration should be performed in the dark
(nifedipine, nicardipine, metronidazole, amiodarone,
furosemide) [75].
Little is known about interactions of many other
drugs that may be used in patients with renal failure
undergoing tube feeding. Hence, close monitoring of
the plasma drug levels, treatment response, and compat-
ibility with the formula are necessary.
References
[1] Nagata M, Osumi Y. Central alpha-2-adrenoreceptor-mediated
inhibition of grastric motility in rats. Jpn J Pharmacol
1993;62:329e30.
[2] Baba T, Ishizaki T. Recent advances in pharmacological
management of hypertension in diabetic patients with
nephropathy. Effects of antihypertensive drugs on kidney
function and insulin sensitivity. Drugs 1992;43:464e89.
[3] Bailey DG. Fruit juice inhibition of uptake transport: a new
type of food-drug interaction. Br J Clin Pharmacol 2010;70:
645e55.
[4] Greenblatt DJ. Analysis of drug interactions involving fruit
beverages and organic anion-transporting polypeptides. J Clin
Pharmacol 2009;49:1403e7.
[5] Wienk KJ, Marx JJ, Lemmens AG, et al. Mechanism underlying
the inhibitory effect of high calcium carbonate intake on iron
bioavailability from ferrous sulphate in anaemic rats. Br J Nutr
1996;75:109e20.
[6] Touchette M, Slaughter R. The effect of renal failure on hepatic
drug clearance. DICP 1991;25:1214e24.
[7] Anderson K, Conney A, Kappas A. Nutrition and oxidative
drug metabolism in man: Relative influence of dietary lipids,
carbohydrates, and protein. Clin Pharmacol Ther
1979;26:493e501.
[8] Fagan T, Walle T, Oexmann M, et al. Increased clearance of
propranolol and theophylline by high-protein compared
with high-carbohydrate diet. Clin Pharmacol Ther 1987;41:
402e6.
[9] Berlinger W, Park G, Spector R. The effect of dietary protein on
the clearance of allopurinol and oxypurinol. N Engl J Med
1985;313:771e6.
[10] Pantuck E, Pantuck C, Anderson K, et al. Effect of brussels
sprounts and cabbage on drug conjugation. Clin Pharmacol
Ther 1984;35:161e9.
[11] Yang C, Brady J, Hong J. Dietary effects on cytochromes P-450,
xenobiotic metabolism, and toxicity. FASEB J 1992;6:737e44.
 DRUGeNUTRIENT INTERACTIONS IN RENAL FAILURE
[12] Vang O, Jensen M, Autrup H. Induction of cytochrome P450
1A1 in rat colon and liver by indole-3-carbinol and 5,6-benzo-
flavone. Carcinogenesis 1990;11:1259e63.
[13] Evarts R, Mostafa M. Effects of indole and tryptophane on
cytochrome P-450, dimethylnitrosamine demethylase, and
arylhydrocarbon hydroxylase activities. Biochem Pharmacol
1981;30:517e22.
[14] Yoo J, Park H, Ning S, et al. Effects of thiamine deficiency on
hepatic cytochromes P450 and drug-metabolizing enzyme
activities. Biochem Pharmacol 1990;39:519e25.
[15] Fuhr U. Drug interactions with grapefruit juice. Extent, prob-
able mechanism and clinical relevance. Drug Safety
1998;18:251e72.
[16] Tassaneeyakul W, Guo LQ, Fukuda K, et al. Inhibition selec-
tivity of grapefruit juice components on human cytochromes
P450. Arch Biochem Biophys 2000;378:356e63.
[17] Kimura Y, Ito H, Ohnishi R, et al. Inhibitory effects of poly-
phenols on human cytochrome P450 3A4 and 2C9 activity. Food
Chem Toxicol 2010;48:429e35.
[18] Bailey DG, Arnold JM, Munoz C, et al. Grapefruit jui-
ceefelodipine interaction: mechanism, predictability, and effect
of naringin. Clin Pharmacol Therapeut 1993;53:637e42.
[19] Guengerich F, Kim D. In-vitro inhibition of dihydropyridine
oxidation and aflatoxin B1 activation in human liver micro-
somes by naringenin and other flavonoids. Carcinogenesis
1990;11:2275e9.
[20] Ozdemir M, Aktan Y, Boydag BS, et al. Interaction between
grapefruit juice and diazepam in humans. Eur J Drug Metab
Pharmacokinet 1998;23:55e9.
[21] Pisarik P. Blood pressure-lowering effect of adding grape-
fruit juice to nifedipine and terazosin in a patient with
severe renovascular hypertension. Arch Fam Med 1996;5:
413e6.
[22] Houston J. Effect of vitamin C supplement on antipyrine
disposition in man. Br J Clin Pharmacol 1977;4:236e9.
[23] Shigetomi S, Kuchel O. Defective 3,4-dihydroxyphenylalanine
decarboxylation to dopamine in hydralazine-treated hyperten-
sive patients may be pyridoxine remedial. Am J Hypertension
1993;6:33e40.
[24] Brater D. Clinical pharmacology of loop diuretics in health and
disease. Eur Heart J 1992;13:10e4.
[25] Fillastre J, Montay G, Bruno R, et al. Pharmacokinetics of
sparfloxacin in patients with renal impairment. Animicrob
Agents Chemother 1994;38:733e7.
[26] Dreisbach AW, Lertora JJ. The effect of chronic renal failure on
drug metabolism and transport. Expert Opin Drug Metab
Toxicol 2008;4:1065e74.
[27] Lamy P. Effects of diet and nutrition on drug therapy. J Am
Geriatr Soc 1982;30:S99eS112.
[28] Roe D. Therapeutic significance of drugenutrient interactions
in the elderly. Pharmacol Rev 1984;36:109Se22S.
[29] Botez M, Botez T, Ross-Chouinard A, et al. Thiamine and folate
treatment in chronic epileptic patients: A controlled study with
the Wechsler IQ scale. Epilepsy Res 1993;16:157e63.
[30] McCune R, Deuschle K, McDermott W. The delayed appearance
of isoniazid antagonism by pyridoxine in-vivo. Ann Rev Tuberc
1957;76:1106e9.
[31] Kappus H, Diplock A. Tolearance and safety of vitamin E: A
toxicological position report. Free Radical Biol Med
1992;13:55e74.
[32] Golper T, Hartstein A, Morthland V, et al. Effects of antacids
and dialysis dwell times on multiple-dose pharmacokinetics of
oral ciprofloxacin in patients on continuous ambulatory peri-
toneal dialysis. Antimicrob Agents Chemother 1987;31:
1787e90.
737
[33] Nix D, Watson W, Lerner M, et al. Effects of aluminum and
magnesium antacids and ranitidine on the absorption of
ciprofloxacin. Clin Pharmacol Therapeut 1989;46:700e5.
[34] Redandt J, Marchbanks C, Dudley M. Interactions of fluo-
roquinolones with other drugs: Mechanisms, variability, clinical
significance and management. Clin Infect Dis 1992;14:272e84.
[35] Deppermann K, Lode H. Fluoroquinolones: Interaction profile
during enteral absorption. Drugs 1993;45:65e72.
[36] Naito E, Ito M, Takeda E, et al. Molecular analysis of abnormal
pyruvate dehydrogenase in a patient with thiamine-responsive
congenital lactic acidosis. Pediatr Res 1994;36:340e6.
[37] Sanz Parı́s A, Albero Gamoa R, Acha Pérez FJ, et al. Thiamine
deficiency associated with parenteral nutrition: apropos of
a new case. Nutricion Hosp 1994;9:110e3.
[38] Hamalatha S, Kerr D, Wexler I, et al. Pyruvate dehydrogenase
complex deficiency due to a point mutation (P188L) within the
thiamine pyrophosphate binding loop of the E1 alpha subunit.
Hum Mol Gen 1995;4:315e8.
[39] Force R, Nahata M. Effect of histamine H2-receptor antagonists
on vitamin B12 absorption. Ann Pharmacother 1992;26:1283e6.
[40] Palopoli J, Waxman J. Recurrent aphthous stomatitis and
vitamin B12 deficiency. South Med J 1990;83:475e7.
[41] Carl G, Smith M. Phenytoin-folate interaction: Differing effects
of the sodium salt and the free acid of phenytoin. Epilepsia
1992;33:372e6.
[42] Casserly C, Stange K, Chren M. Severe megaloblastic anemia in
a patient receiving low dose methotrexate for psoriasis. J Am
Acad Dermatol 1993;29:477e80.
[43] Elmazar M, Nau H. Trimetoprim potentiates valproic acid-
induced neural tube defects in mice. Reprod Toxicol
1993;7:249e54.
[44] Baylis E, Crowley J, Preece J, et al. Influence of folic acid on
blood phenytoin levels. Lancet 1971;1:62e4.
[45] Shah I, Whiting P, Omar G, et al. The effects of retinoids and
terbinafine on the human microsomal metabolism of cyclo-
sporine. Br J Dermatol 1993;129:395e8.
[46] Kaiser C, McAuliffe J, Barth R, et al. Hypoprothrombinemia and
hemorrhage in a surgical patient treated with cefotetan. Arch
Surg 1991;126:524e5.
[47] Kikuchi S, Ando A, Minato K. Acquired coagulopathy caused
by administration of parenteral broard spectrum antibiotics. Jpn
J Clin Pathol 1991;39:83e90.
[48] Westphal J, Vetter D, Brogard J. Hepatic side-effects of antibi-
otics. J Antimicrob Chemother 1994;33:387e401.
[49] Zerwekh J, Homan R, Tindall R, et al. Decreased serum 24, 25-
dihydroxyvitamin D concentration during long-term anticon-
vulsant therapy in adult epileptics. Ann Neurol 1982;12:184e6.
[50] Kopple J, Hirschberg R. Nutrition and peritoneal dialysis. In:
Mitch W, Klahr S, editors. Nutrition and the Kidney. Boston:
Little, Brown and Company; 1993. p. 290e313.
[51] Shirley D, Singer D, Sagnella G, et al. Effect of a single test dose
of lithium carbonate on sodium and potassium excretion in
man. Clin Sci 1991;81:59e63.
[52] Murphy M, Lewis P, Kohner E, et al. Glucose intolerance in
hypertensive patients treated with duretics. A 14 year follow-up.
Lancet 1982;2:1293e5.
[53] Race T, Paes I, Faloon W. Intestinal malabsorption induced by
oral colchicine. comparison with neomycin and cathartic
agents. Am Med Sci 1981;259:32e41.
[54] Eknoyan G, Suki W, Martinez-Maldonato M. Effect of diuretics
on urinary excretion of phosphate, calcium and magnesium in
thyroparathyroidectomized dogs. J Lab Clin Med 1970;76:
257e66.
[55] Newmark K, Nugent P. Milk-alkali syndrome: A consequence
of chronic antacid abuse. Postgrad Med 1993;93. 149e150 & 156.
738 NUTRITIONAL MANAGEMENT OF RENAL DISEASE
[56] Mitwalli A, Oreopoulos D. Hyperoxaluria and hyperoxalemia:
One more concern for the nephrologist. Int J Artific Org
1985;8:71e4.
[57] Chen W, Chiang T, Chen T. Serum zinc and copper during long-
term parenteral nutrition. J Formosan Med Assoc
1991;90:1075e80.
[58] Milanino R, Frigo A, Bambara L, et al. Copper and zinc status in
rheumatoid arthritis: Studies of plasma, erythrocytes, and urine
and their relationship to disease activity markers and phar-
macological treatment. Clin Exp Rheumat 1993;11:271e81.
[59] Goldwasser P, Koutelos T, Abraham S, et al. Serum ferritin,
hematocrit and mean corpuscular volume in hemodialysis.
Nephron 1994;67:30e5.
[60] Schaffer SW, Lombardini JB, Azuma J. Interaction between the
actions of taurine and angiotensin II. Amino Acids
2000;18:305e18.
[61] Cruz CI, Ruiz-Torres P, del Moral RG, et al. Age-related
progressive renal fibrosis in rats and its prevention with ACE
inhibitors and taurine. Am J Physiol Renal Physiol 2000;278:
F122e129.
[62] Franconi F, Bennardini F, Mattana A, et al. Plasma and platelet
taurine are reduced in subjects with insulin-dependent diabetes
mellitus: effects of taurine supplementation. Am J Clin Nutr
1995;61:1115e9.
[63] Zhao X, Jia J, Lin Y. Taurine content in Chinese food and daily
intake of Chinese men. Adv Exp Med Biol 1998;442:501e5.
[64] Stangier J, Eriksson BI, Dahl OE, et al. Pharmacokinetic profile
of the oral direct thrombin inhibitor dabigatran etexilate in
healthy volunteers and patients undergoing total hip replace-
ment. J Clin Pharmacol 2005;45:555e63.
[65] Kubitza D, Becka M, Zuehlsdorf M, et al. Effect of food, an
antacid, and the H2 antagonist ranitidine on the absorption
of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa
inhibitor, in healthy subjects. J Clin Pharmacol 2006;46:
549e58.
[66] Danovitch G. Immunosuppressive medications and protocols
for kidney transplantation. In: Danovitch G, editor. Handbook
of Kidney Transplantation. Boston: Little, Brown and Company;
1992. p. 67e103.
[67] Lindholm A, Henriccson S, Dahlqvist R. The effect of food and
bile acid administration on the relative bioavailability of
cyclosporine. Br J Clin Pharmacol 1990;29:541e8.
[68] Kolars J, Awni W, Merion R, et al. First-pass metabolism of
cyclosporine by the gut. Lancet 1991;338:1488e90.
[69] Fahr A. Cyclosporine clinical pharmacokinetics. Clin Phama-
cokinet 1993;24:472e95.
[70] Christians U, Sewing K. Cyclosporine metabolism in transplant
patients. Pharmacol Ther 1993;57:291e345.
[71] Herlitz H, Edgar B, Hedner T, et al. Grapefruit juice: A possble
source of variability in blood concentrations of cyclosprone A.
Nephr Dial Transpl 1993;8:375.
[72] Brunner LJ, Munar MY, Vallian J, et al. Interaction between
cyclosporine and grapefruit juice requires long-term ingestion
in stable renal transplant recipients. Pharmacotherapy
1998;18:23e9.
[73] Vicari-Christensen M, Repper S, Basile S, et al. Tacrolimus:
review of pharmacokinetics, pharmacodynamics, and pharma-
cogenetics to facilitate practitioners’ understanding and offer
strategies for educating patients and promoting adherence.
Prog Transplant 2009;19:277e84.
[74] Melnik G. Pharmacologic aspects of enteral nutrition. In:
Rombeau J, Coldwell M, editors. Clinical Nutrition: Enteral
and Tube feeding. Philadelphia: W.B. Sauders Company; 1990.
p. 472e509.
[75] Behnken I, Gaschott T, Stein J. [Enteral nutrition: drug admin-
istration via feeding tube]. Z Gastroenterol 2005;43:1231e41.
[76] Au Yeung SC, Ensom MH. Phenytoin and enteral feedings: does
evidence support an interaction? Ann Pharmacother
2000;34:896e905.
[77] Worden J, Wood C, Workman C. Phenytoin and nasogastric
feedings. Neurology 1994;34:132.
[78] Scott D. Addition of potassium supplements to mild-based tube
feedings. J Hum Nutr 1980;34:85e90.
[79] Valli C, Schultheiss H, Asper R, et al. Interaction of nutrients
with antacids: A complication during enteral tube feeding.
Lancet 1986;1:747e8.
[80] Howard P, Hannaman K. Warfarin resistance linked to enteral
nutrition products. J Am Diet Assoc 1985;85:713e5.
[81] Klang M, Graham D, McLymont V. Warfarin bioavailability
with feeding tubes and enteral formula. JPEN J Parenter Enteral
Nutr 2010;34:300e4.
[82] Nimmo W. Drugs, disease and altered gastric emptying. Clin
Pharmacokinet 1976;1:189e203.
[83] Prescott L. Gastric emptying and drug absorption. Br J Clin
Pharmacol 1974;1:189e90.
[84] Couet W, Istin B, Sinuta P, et al. Effect of ponsinomycin on
cyclosporine pharmacokinetics. Eur J Clin Pharmacol
1990;39:165e7.