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 bread, cranberries, plums and prunes. More alkaline
dihydropyridine calcium channel blockers has signifi- urine can be caused by milk, various fruits and all vege-
cant clinical implications. First, the increased plasma tables except corn and lentils [28].
levels of the drugs may raise the incidence of adverse
effects. Second, in hypertensive patients treated with
dihydropyridines, sporadic concomitant ingestion of INTERACTIONS OF FOOD
grapefruit juice may cause symptomatic hypotension. SUPPLEMENTS WITH DRUGS
Third, the combination of a dihydropyridine antihyper-
tensive with grapefruit juice can increase the therapeutic Patients with advanced CKD and those on mainte-
efficacy. This has been illustrated in a published case nance dialysis are often prescribed food supplements,
report [21]. such as vitamins and iron preparations, or phosphate
Large doses of vitamin C given as nutritional supple- binders. Specific interactions between certain drugs
ments to patients without ascorbic acid deficiency may and these food supplements have been described that
increase the rate of oxidative drug metabolism [22]. may not only reduce the blood levels of the drug but
High vitamin C intakes can also reduce the rate of may reduce the drug efficacy. Thus, it may be necessary
sulfate conjugation of drugs, such as acetaminophen, to separate the timing of the intake of the food supple-
by competing for the available sulfate. Dietary supple- ment from that of the drug. In general, the drug should
mentation with large doses of pyridoxine may increase be taken one hour before or two hours after the supple-
the metabolism and decrease the therapeutic efficacy ment, but in some circumstances this period of time
of levodopa, since this vitamin is a cofactor for the should be even longer (up to 4 h).
dopa decarboxylase [23]. In contrast, St. John’s Wort Supplemental folic acid decreases the blood levels of
induces CYP3A4 and accelerates metabolism of some phenobarbital [29] and may lead to break-through
drugs. 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
Nutrients and Urinary Excretion of Drugs
pyridoxal phosphate-dependent enzymes. In animal
The deficiency in some trace elements such as iron, experiments, large doses of pyridoxine may reduce the
zinc, copper, and selenium has been shown to influence activity of isonicotinic acid against tuberculosis. Pyri-
the mixed function oxidase system in experimental doxine appears to form a Schiff base with isonicotinic
animals, but for most such elements, studies in humans acid which is then excreted in the urine or removed
are not available. Moreover, even marked iron defi- during dialysis [30]. Concomitant therapy with pyri-
ciency in man does not appear to affect oxidative drug doxine and L-dopa in patients with Parkinson’s disease
metabolism. reduces the efficacy of the latter drug and worsens the
In CKD the half-life of drugs that are primarily disease symptoms.
metabolized by hepatic glucuronidation may be pro- Excess intake of vitamin E can induce a hemorrhagic
longed [24,25]. There is circumstantial evidence that state in laboratory animals caused by vitamin K defi-
renal insufficiency per-se reduces hepatic drug clearance ciency [31]. Patients on Coumadin therapy are at risk
[26]. Although it is possible that fasting, malnutrition or for developing hemorrhages that result from unwar-
specific nutrient deficiencies may alter the hepatic glu- ranted further suppression of the vitamin K-dependent
curonidation of some drugs, the literature at present clotting factors by concomitant intake of vitamin E. It
does not provide clearly supportive data. has been suggested that megadoses of vitamin C
The urinary excretion of certain drugs or of bioactive (>1 g/day) may lead to vitamin B12 deficiency appar-
or toxic metabolites does not only depend on the degree ently by destruction of vitamin B12 by vitamin C when
of renal failure, i.e. GFR or creatinine clearance, but also they are taken together.
on urinary pH [27]. In patients with normal renal func- Clinically important interactions occur between iron
tion and even in patients with moderate or even supplements or phosphate binders and fluoroquino-
advanced CKD, urinary pH depends largely on dietary lone antibiotics [32]. Bioavailability of ciprofloxacin is
intakes, at least during the post-absorptive period. A reduced if the drug is co-administered with aluminum
low protein diet produces more alkaline urine, and hydroxide-containing phosphate binders. Magnesium
conversely, a high protein diet results in more acidic hydroxide as well as aluminum hydroxide reduce the
urine. Drugs or drug metabolites that are weak bases bioavailability of ciprofloxacin by as much as 90%
are more efficiently excreted in acidic urine, whereas when given concomitantly or within <0.5 hours, and
more alkaline urine will promote the excretion of drugs a lesser but still significant reduction occurs when
or metabolites that are weak acids. Foods that poten- the drug is given within up to 4 hours after the antacid
tially acidify the urine include meats, fish, eggs, cheese, [33]. Similar reductions in the bioavailability occur for
 DRUGeNUTRIENT INTERACTIONS IN RENAL FAILURE 733
other fluoroquinolone antibiotics, such as norfloxacin, Several drugs antagonize folic acid and may cause
ofloxacin and enoxacin when administered up to four megaloblastic anemia. These include phenytoin, pheno-
hours after intake of aluminum, magnesium or calcium barbital, sulphasalazine, triamterene, trimethoprim, tri-
containing phosphate binders [34]. A significant metrexate and methotrexate [41e43]. On the other
decrease in the bioavailability of fluoroquinolones hand, folate supplementation may interact with these
was also described by several authors to occur upon medicines and reduce their clinical efficacy. Daily
co-administration with several oral iron supplement dosages of folate of more than 5 mg reduces the plasma
preparations such as ferrous sulfate, fumarate or levels of phenytoin and phenobarbital and may reduce
gluconate. Calcium-containing phosphate binders or their therapeutic efficacy [44]. A risk for the develop-
antacids have also been shown to reduce the bioavail- ment of niacin deficiency may exist when treatment
ability of tetracyclines [35]. Sevelamer does not appear with isoniazid is prescribed. During such treatment,
to have such effects on drug bioavailability. The reduc- concurrent administration of niacin (100 mg/day) may
tion of iron absorption from diet or ferrous sulfate due be advisable. Retinoids and possibly retinol increase
to co-administration of calcium-containing phosphate the blood cyclosporine levels [45]. Vitamin A supple-
binders has been discussed earlier in this chapter. 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
DRUG-INDUCED NUTRITIONAL may induce or enhance severe bleeding. This has been
DEFICIENCIES described particularly with the administration of moxa-
lactam, cefotetan, cefamandole, cefoperazone and other
Several prescribed or over-the-counter medicines cephalosporins that contain the methylthiotetrazole side
reduce appetite and food intake. In patients with CKD chain. Vitamin K supplements should be administered
or on maintenance dialysis this may aggravate an concurrently with these antibiotics [46,47]. Weaker
already poor nutritional status and may contribute to anti-vitamin K effects have been shown with tetracycline
frank malnutrition. However, of greater concern are and cholestyramine [48]. Ingestion of megadoses of
more specific interactions of prescribed drugs with vitamin E can cause vitamin K deficiency and should
micronutrients, mainly with certain vitamins and be avoided [31].
minerals. Drug-induced osteomalacia can be due to chronic
intake of anticonvulsants, isoniazid and possibly cimeti-
dine. Anticonvulsant therapy with phenytoin, phenobar-
Drug-Induced Vitamin Deficiencies bital, or carbamazepine results in reduced levels of 24,25-
Vitamin metabolism and requirements in renal dihydroxyvitamin D3, and this may play a role in the
disease and renal failure are described in Chapter anticonvulsant-induced osteomalacia [49]. In patients
24. Thiamine deficiency may be aggravated or caused with CKD this drug-induced risk for osteomalacia may
by chronic alcoholism. The literature, at present, does be additive to the increased risk of renal bone disease.
not suggest that specific short-term or long-term drug Patients undergoing chronic dialysis therapy are often
therapies may cause vitamin B1 deficiency. However, supplemented with 1,25-dihydroxycholecalciferol or
thiamine deficiency may occur in severely ill patients analogues. However, in patients with moderate CKD
who undergo parenteral nutrition [36,37]. Thiamine is not receiving 1,25-dihydroxycholecalciferol, vitamin D
a co-enzyme for pyruvate dehydrogenase, and thia- supplements should be given concurrently with the
mine deficiency may cause the acute onset of unex- above drug treatments.
plained, severe lactic acidosis [36e38]. Riboflavin
deficiency can be caused or aggravated by long-term Drug-Induced Mineral and Trace Element
administration of chlorpromazine or amitriptyline.
Pyridoxine deficiency may be caused by long-term
Deficiencies
treatment with isoniazid. It is recommended that As a rule, the intakes of many minerals such as Na, K,
vitamin B6 supplements (10e15 mg/day) should be Mg, Ca and P correlate with the intake of nitrogen [50].
prescribed for the entire period of time that isoniazid Mineral and trace element deficiencies may develop due
is taken. Vitamin B6 deficiency may also be caused by to poor nutritional intakes and elderly patients are at
hydralazine and penicillamine [23]. High doses of greater risk. Mineral depletion can occur due to poor
pyridoxine hydrochloride reduce the serum levels gastrointestinal absorption and/or enhanced renal
of anticonvulsants and may reduce the clinical seizure excretion, the latter mainly in patients with lesser
control. Chronic vitamin B12 deficiency may develop degrees of CKD. Both, reduced absorption and
during long-term treatment with colchicine or enhanced excretion of minerals can be caused by drug
cimetidine [39,40]. therapy. Potassium, calcium, magnesium, iron and zinc
734 NUTRITIONAL MANAGEMENT OF RENAL DISEASE

are the most common minerals that become depleted in symptoms that are often observed in patients with
patients with CKD. Drug-induced potassium deficiency CKD, such as loss of appetite and altered taste and
in patients with chronic renal failure most commonly smell sensation. Loss of taste or smell may lead to
results from diuretic therapy and can be caused by reduced food intake and, hence, malnutrition. Aspirin
both thiazide and loop diuretics. With diuretic therapy, (even at the low dose of 81 mg/day), ibuprofen and
magnesium deficiency may also develop. other non-steroidal anti-inflammatory drugs may
Concurrent intake of aminoglycosides and cephalo- cause occult gastrointestinal bleeding and contribute
sporin antibiotics can be interactive and cause potas- to iron losses [59]. Iron depletion and anemia may
sium (and magnesium) depletion, particularly when also be caused by poor food intake or reduced
intakes of these minerals are low which may occur bioavailability from non-heme iron in foods such as
with ingestion of low protein diets. Hypokalemia can due to concomitant calcium-containing phosphate
also occur with gentamycin toxicity and during treat- binders. This has been discussed above. There are
ment with amphotericin B. Potassium deficiency may not sufficient data to indicate whether there are impor-
also be caused by laxative abuse with resulting potas- tant drug interactions with other trace elements, such
sium losses through the gastrointestinal tract. Lithium as selenium, molybdenum, chromium, manganese,
carbonate and levodopa can contribute to potassium rubidium and others.
deficiency [51]. Hypokalemia and potassium depletion
worsen blood pressure levels in hypertensive patients
and may contribute to the thiazide-induced carbohy- TAURINE AND ACE-INHIBITOR
drate intolerance [52]. EFFECTS
Calcium deficiency can be caused by poor dietary
intake, primary malabsorption or vitamin D-deficiency- The amino acid taurine blocks actions of angiotensin
induced malabsorption, or drug-induced hypercalciuria. II by inhibiting cellular Caþþ-uptake and angiotensin II
Primary calcium malabsorption can result from enterop- signaling [60]. In experimental in-vitro and in-vivo
athy caused by neomycin, colchicine, methotrexate and studies taurine food supplements were found to have
corticosteroids [53]. Aluminum and magnesium renal antifibrogenic effects comparable to those of
hydroxide may reduce calcium absorption. Phenytoin ACE-inhibitors [61].
and phenobarbital may interfere with vitamin D metabo- Serum and blood cell taurine levels tend to be lower
lism as described above. Loop diuretics, such as furose- in diabetics compared to normal subjects and taurine
mide and ethacrynic acid can cause hypocalcemia food supplements can normalize taurine levels [62].
secondary to hypercalciuria [54]. In patients with chronic Foods rich in taurine include seafood, particularly crus-
renal failure combined treatments with drugs that inter- taceans and molluscs, and lesser amounts are present in
fere with calcium metabolism are not uncommon. beef, pork and lamb [63]. Taurine containing food
Hypercalcemia in patients with CKD may result in supplements are available over the counter. Whether
soft tissue calcification and nephrocalcinosis that may increased dietary taurine will indeed reduce the
contribute to the progression of renal disease or may progression of renal disease and/or reduce the cardio-
itself cause CKD. The long-term combined intakes of vascular mortality in chronic dialysis patients is
large amounts of calcium carbonate and (vitamin unknown due to the lack of respective clinical trials.
D-fortified) milk can lead to severe chronic hypercal- Nevertheless, this may be an example of collaborative,
cemia and nephrocalcinosis causing CKD, the so-called beneficial drugenutrient interaction.
milk-alkali syndrome [55]. In CKD, hypercalcemia may
result from the intake of calcium-containing phosphate
binders and/or vitamin D derivatives. NUTRIENT INTERACTIONS WITH
Hyperoxalemia and hyperoxaluria can be caused or ORAL ANTICOAGULANTS
aggravated by vitamin C supplementation, even at
moderate doses (i.e., 500 mg/day) [56]. Patients who Until recently, Coumadin was the mainstay of oral
eat relatively large amounts of foods that generate anticoagulation therapy in non-renal as well as CKD-
oxalate (e.g., green salads) and take moderate or mega- patients. This drug is a prime example of the importance
doses of vitamin C have an increased risk to develop of foods that can interfere with drug actions. This is
hyperoxalemia-associated complications [56]. mainly because of the small therapeutic window
Zinc deficiency may be caused or worsened by total between under- and overdose as well as its reduced effi-
parenteral nutrition without adequate zinc intake [57]. cacy by dietary vitamin K intakes. Table 44.5 summarizes
Administration of penicillamine or corticosteroids commonly consumed foods with relatively high vitamin
have also been associated with zinc deficiency [58]. K content. In contrast, the intake of large amounts of
Zinc depletion causes or contributes to clinical vitamin E can cause vitamin K deficiency [31].
 DRUGeNUTRIENT INTERACTIONS IN RENAL FAILURE 735
TABLE 44.5 Commonly Consumed Foods High in Vitamin K caused by metabolism in the small bowel wall [68].
Content Cyclosporine is metabolized by oxidation in liver micro-
somes through the cytochrome P-450 3A isoenzyme
Beef liver Cheese Lettuce
system [69]. This enzyme system is also expressed in
Broccoli Collard greens Spinach the small bowel wall which explains the first-pass
Brussels sprouts Green tea Soybean metabolism of cyclosporine A [70].
Cyclosporine A is a highly lipid-soluble drug, and
Cabbage Lentils Turnip greens
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
Several novel orally effective small molecule factor Xa gastrointestinal absorption and plasma levels of cyclo-
or thrombin enzyme inhibitor anticoagulants have sporine A but this has not been confirmed in clinical
recently been approved by regulatory agencies (rivarox- trials.
aban, dabigatran) or are in various stages of clinical and As indicated above, citrus juices, particularly grape-
registrative development in the US and Europe (apica- fruit juice, reduce the metabolic rate of Cyclosporine
ban, edoxaban, betrixaban). Rivaroxaban and dabiga- and raise its blood levels [71], possibly through the
tran are approved for patients with CKD stages 1-3B inhibitory effects of flavonoids and other compounds
but not or only with caution in CKD 4 and 5. High fat, on cytochrome P-450 3A enzymes [15]. The inhibition
high calorie diets tend to reduce the rate of absorption of CYP3A4 by grapefruit juice and other citrus juices
of dabigatran but overall drug availability is not and fruits raises the area-under-the-curve and causes
substantially different from fasting [64]. Similar food an increase in the 24 hr trough cyclosporine level [72].
interactions were shown for rivaroxaban [65]. Other St. John’s Wort and caspofungin induces CYP3A4
important food interactions have not yet emerged. Since activity. Other drugs that inhibit or reduce cyclosporine
these drugs are in clinical use for only a short period of A levels due to effects on CYP3A are listed in Tables 44.6
time, other drug nutrient interactions may come to and 44.7.
attention. Both cyclosporine and tacrolimus can cause a number
Apixaban, edoxaban and rivaroxaban are mainly of metabolic complications including phosphorous,
metabolized through CYP3A4. Thus, nutrients and
food supplements that induce CYP3A4 such as St. John’s TABLE 44.6 Drugs that Increase Blood Cyclo-
Wort might reduce drug levels and anticoagulant effi- sporine A Levels Due to Inhibition
cacy. Over-anticoagulation could occur with large of or Competition with CYP3A
amounts of citrus juice intake due to CYP3A4 inhibition. Isoenzymes1
Thus far, this has not materialized. Betrixaban and dabi- Ceftazidime Ketoconazole
gatran are not metabolized by CYP450 enzymes.
Cimetidine Nicardipine
Diltiazem Norfloxacin
INTERACTIONS OF CALCINEURIN Erythromycin Omeprazole
INHIBITORS WITH NUTRIENTS 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, enteral formulas can lead to precipitation of formula
glucose intolerance and diabetes mellitus and hyperli- proteins with the aluminum salts and gastrointestinal
poproteinemia. Tacrolimus is mainly metabolized plug formation can occur [79]. Case reports have sug-
through CYP3A enzymes. Hence, food/food supple- gested that enteral tube feeding causes resistance to
ment interactions can affect tacrolimus blood levels: St. warfarin [79,80]. Apparently, this results from the antag-
John’s Wort (as well as caspofungin) induces CYP3A onistic effect of vitamin K that is present in enteral
and may decrease tacrolimus blood levels. Grapefruit formulas [74]. In patients undergoing treatment with
juice which blocks this enzyme system increases blood warfarin, a formula with a lesser vitamin K content
levels. Drug inhibitors of CYP3A (calcium channel should be used and will improve the response to
blockers and azoles) can increase tacrolimus levels. warfarin. There is also evidence that warfarin may
Absorption of tacrolimus from the gastrointestinal directly bind to the feeding tube reducing drug avail-
tract is substantially influenced by food: Absorption is ability [81]. Some drug compounds are light sensitive
greatest with fasting. High fat diets reduce tacrolimus and inactivated by light exposure and preparation and
absorption and drug availability more than high carbo- tube administration should be performed in the dark
hydrate diets [73]. (nifedipine, nicardipine, metronidazole, amiodarone,
furosemide) [75].
Little is known about interactions of many other
ENTERAL TUBE FEEDING AND ORAL drugs that may be used in patients with renal failure
DRUG ADMINISTRATION undergoing tube feeding. Hence, close monitoring of
the plasma drug levels, treatment response, and compat-
Enteral tube feeding may be a necessary or desirable ibility with the formula are necessary.
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, References
drugs may be administered preferably by intravenous
[1] Nagata M, Osumi Y. Central alpha-2-adrenoreceptor-mediated
routes, but enteral drug administration sometimes may
inhibition of grastric motility in rats. Jpn J Pharmacol
be necessary, since many medicine preparations are 1993;62:329e30.
not available for intravenous infusion. [2] Baba T, Ishizaki T. Recent advances in pharmacological
Several considerations should be taken into account management of hypertension in diabetic patients with
when giving oral drug preparations through enteral nephropathy. Effects of antihypertensive drugs on kidney
function and insulin sensitivity. Drugs 1992;43:464e89.
feeding tubes. First, oral medicines should be delivered
[3] Bailey DG. Fruit juice inhibition of uptake transport: a new
into the stomach to ensure proper preparation for subse- type of food-drug interaction. Br J Clin Pharmacol 2010;70:
quent drug absorption in the jejunum. Second, drugs 645e55.
should be used in liquid form rather than as crushed [4] Greenblatt DJ. Analysis of drug interactions involving fruit
tablets. Third, slow-release or enteric-coated tablets beverages and organic anion-transporting polypeptides. J Clin
Pharmacol 2009;49:1403e7.
should not be crushed at all. Fourth, drugs may not be
[5] Wienk KJ, Marx JJ, Lemmens AG, et al. Mechanism underlying
compatible with the tube feeding formula and should the inhibitory effect of high calcium carbonate intake on iron
not be mixed with formula. Thus, tubes should be bioavailability from ferrous sulphate in anaemic rats. Br J Nutr
flushed with water before and after drug administration. 1996;75:109e20.
Fifth, the osmolality of some liquid drug preparations [6] Touchette M, Slaughter R. The effect of renal failure on hepatic
drug clearance. DICP 1991;25:1214e24.
may be very high and may add to the osmolality of
[7] Anderson K, Conney A, Kappas A. Nutrition and oxidative
the formula. A complete list of commercially available drug metabolism in man: Relative influence of dietary lipids,
liquid preparations of commonly used drugs has been carbohydrates, and protein. Clin Pharmacol Ther
published elsewhere [74,75]. 1979;26:493e501.
Only few studies have examined the bioavailability of [8] Fagan T, Walle T, Oexmann M, et al. Increased clearance of
propranolol and theophylline by high-protein compared
drugs when administered with enteral formulas, and
with high-carbohydrate diet. Clin Pharmacol Ther 1987;41:
this information is not available for most medicines. 402e6.
Phenytoin bioavailability, for example, is much reduced [9] Berlinger W, Park G, Spector R. The effect of dietary protein on
when given with enteral formulas as compared to the clearance of allopurinol and oxypurinol. N Engl J Med
a similar dose given orally [76,77]. Effervescent potas- 1985;313:771e6.
[10] Pantuck E, Pantuck C, Anderson K, et al. Effect of brussels
sium tablet preparations causes marked coagulation of
sprounts and cabbage on drug conjugation. Clin Pharmacol
the enteral formula, whereas potassium chloride or Ther 1984;35:161e9.
gluconate solutions are compatible [78]. Administration [11] Yang C, Brady J, Hong J. Dietary effects on cytochromes P-450,
of aluminum-containing phosphate binders with some xenobiotic metabolism, and toxicity. FASEB J 1992;6:737e44.
 DRUGeNUTRIENT INTERACTIONS IN RENAL FAILURE 737
[12] Vang O, Jensen M, Autrup H. Induction of cytochrome P450 [33] Nix D, Watson W, Lerner M, et al. Effects of aluminum and
1A1 in rat colon and liver by indole-3-carbinol and 5,6-benzo- magnesium antacids and ranitidine on the absorption of
flavone. Carcinogenesis 1990;11:1259e63. ciprofloxacin. Clin Pharmacol Therapeut 1989;46:700e5.
[13] Evarts R, Mostafa M. Effects of indole and tryptophane on [34] Redandt J, Marchbanks C, Dudley M. Interactions of fluo-
cytochrome P-450, dimethylnitrosamine demethylase, and roquinolones with other drugs: Mechanisms, variability, clinical
arylhydrocarbon hydroxylase activities. Biochem Pharmacol significance and management. Clin Infect Dis 1992;14:272e84.
1981;30:517e22. [35] Deppermann K, Lode H. Fluoroquinolones: Interaction profile
[14] Yoo J, Park H, Ning S, et al. Effects of thiamine deficiency on during enteral absorption. Drugs 1993;45:65e72.
hepatic cytochromes P450 and drug-metabolizing enzyme [36] Naito E, Ito M, Takeda E, et al. Molecular analysis of abnormal
activities. Biochem Pharmacol 1990;39:519e25. pyruvate dehydrogenase in a patient with thiamine-responsive
[15] Fuhr U. Drug interactions with grapefruit juice. Extent, prob- congenital lactic acidosis. Pediatr Res 1994;36:340e6.
able mechanism and clinical relevance. Drug Safety [37] Sanz Parı́s A, Albero Gamoa R, Acha Pérez FJ, et al. Thiamine
1998;18:251e72. deficiency associated with parenteral nutrition: apropos of
[16] Tassaneeyakul W, Guo LQ, Fukuda K, et al. Inhibition selec- a new case. Nutricion Hosp 1994;9:110e3.
tivity of grapefruit juice components on human cytochromes [38] Hamalatha S, Kerr D, Wexler I, et al. Pyruvate dehydrogenase
P450. Arch Biochem Biophys 2000;378:356e63. complex deficiency due to a point mutation (P188L) within the
[17] Kimura Y, Ito H, Ohnishi R, et al. Inhibitory effects of poly- thiamine pyrophosphate binding loop of the E1 alpha subunit.
phenols on human cytochrome P450 3A4 and 2C9 activity. Food Hum Mol Gen 1995;4:315e8.
Chem Toxicol 2010;48:429e35. [39] Force R, Nahata M. Effect of histamine H2-receptor antagonists
[18] Bailey DG, Arnold JM, Munoz C, et al. Grapefruit jui- on vitamin B12 absorption. Ann Pharmacother 1992;26:1283e6.
ceefelodipine interaction: mechanism, predictability, and effect [40] Palopoli J, Waxman J. Recurrent aphthous stomatitis and
of naringin. Clin Pharmacol Therapeut 1993;53:637e42. vitamin B12 deficiency. South Med J 1990;83:475e7.
[19] Guengerich F, Kim D. In-vitro inhibition of dihydropyridine [41] Carl G, Smith M. Phenytoin-folate interaction: Differing effects
oxidation and aflatoxin B1 activation in human liver micro- of the sodium salt and the free acid of phenytoin. Epilepsia
somes by naringenin and other flavonoids. Carcinogenesis 1992;33:372e6.
1990;11:2275e9. [42] Casserly C, Stange K, Chren M. Severe megaloblastic anemia in
[20] Ozdemir M, Aktan Y, Boydag BS, et al. Interaction between a patient receiving low dose methotrexate for psoriasis. J Am
grapefruit juice and diazepam in humans. Eur J Drug Metab Acad Dermatol 1993;29:477e80.
Pharmacokinet 1998;23:55e9. [43] Elmazar M, Nau H. Trimetoprim potentiates valproic acid-
[21] Pisarik P. Blood pressure-lowering effect of adding grape- induced neural tube defects in mice. Reprod Toxicol
fruit juice to nifedipine and terazosin in a patient with 1993;7:249e54.
severe renovascular hypertension. Arch Fam Med 1996;5: [44] Baylis E, Crowley J, Preece J, et al. Influence of folic acid on
413e6. blood phenytoin levels. Lancet 1971;1:62e4.
[22] Houston J. Effect of vitamin C supplement on antipyrine [45] Shah I, Whiting P, Omar G, et al. The effects of retinoids and
disposition in man. Br J Clin Pharmacol 1977;4:236e9. terbinafine on the human microsomal metabolism of cyclo-
[23] Shigetomi S, Kuchel O. Defective 3,4-dihydroxyphenylalanine sporine. Br J Dermatol 1993;129:395e8.
decarboxylation to dopamine in hydralazine-treated hyperten- [46] Kaiser C, McAuliffe J, Barth R, et al. Hypoprothrombinemia and
sive patients may be pyridoxine remedial. Am J Hypertension hemorrhage in a surgical patient treated with cefotetan. Arch
1993;6:33e40. Surg 1991;126:524e5.
[24] Brater D. Clinical pharmacology of loop diuretics in health and [47] Kikuchi S, Ando A, Minato K. Acquired coagulopathy caused
disease. Eur Heart J 1992;13:10e4. by administration of parenteral broard spectrum antibiotics. Jpn
[25] Fillastre J, Montay G, Bruno R, et al. Pharmacokinetics of J Clin Pathol 1991;39:83e90.
sparfloxacin in patients with renal impairment. Animicrob [48] Westphal J, Vetter D, Brogard J. Hepatic side-effects of antibi-
Agents Chemother 1994;38:733e7. otics. J Antimicrob Chemother 1994;33:387e401.
[26] Dreisbach AW, Lertora JJ. The effect of chronic renal failure on [49] Zerwekh J, Homan R, Tindall R, et al. Decreased serum 24, 25-
drug metabolism and transport. Expert Opin Drug Metab dihydroxyvitamin D concentration during long-term anticon-
Toxicol 2008;4:1065e74. vulsant therapy in adult epileptics. Ann Neurol 1982;12:184e6.
[27] Lamy P. Effects of diet and nutrition on drug therapy. J Am [50] Kopple J, Hirschberg R. Nutrition and peritoneal dialysis. In:
Geriatr Soc 1982;30:S99eS112. Mitch W, Klahr S, editors. Nutrition and the Kidney. Boston:
[28] Roe D. Therapeutic significance of drugenutrient interactions Little, Brown and Company; 1993. p. 290e313.
in the elderly. Pharmacol Rev 1984;36:109Se22S. [51] Shirley D, Singer D, Sagnella G, et al. Effect of a single test dose
[29] Botez M, Botez T, Ross-Chouinard A, et al. Thiamine and folate of lithium carbonate on sodium and potassium excretion in
treatment in chronic epileptic patients: A controlled study with man. Clin Sci 1991;81:59e63.
the Wechsler IQ scale. Epilepsy Res 1993;16:157e63. [52] Murphy M, Lewis P, Kohner E, et al. Glucose intolerance in
[30] McCune R, Deuschle K, McDermott W. The delayed appearance hypertensive patients treated with duretics. A 14 year follow-up.
of isoniazid antagonism by pyridoxine in-vivo. Ann Rev Tuberc Lancet 1982;2:1293e5.
1957;76:1106e9. [53] Race T, Paes I, Faloon W. Intestinal malabsorption induced by
[31] Kappus H, Diplock A. Tolearance and safety of vitamin E: A oral colchicine. comparison with neomycin and cathartic
toxicological position report. Free Radical Biol Med agents. Am Med Sci 1981;259:32e41.
1992;13:55e74. [54] Eknoyan G, Suki W, Martinez-Maldonato M. Effect of diuretics
[32] Golper T, Hartstein A, Morthland V, et al. Effects of antacids on urinary excretion of phosphate, calcium and magnesium in
and dialysis dwell times on multiple-dose pharmacokinetics of thyroparathyroidectomized dogs. J Lab Clin Med 1970;76:
oral ciprofloxacin in patients on continuous ambulatory peri- 257e66.
toneal dialysis. Antimicrob Agents Chemother 1987;31: [55] Newmark K, Nugent P. Milk-alkali syndrome: A consequence
1787e90. of chronic antacid abuse. Postgrad Med 1993;93. 149e150 & 156.
738 NUTRITIONAL MANAGEMENT OF RENAL DISEASE

[56] Mitwalli A, Oreopoulos D. Hyperoxaluria and hyperoxalemia: [69] Fahr A. Cyclosporine clinical pharmacokinetics. Clin Phama-
One more concern for the nephrologist. Int J Artific Org cokinet 1993;24:472e95.
1985;8:71e4. [70] Christians U, Sewing K. Cyclosporine metabolism in transplant
[57] Chen W, Chiang T, Chen T. Serum zinc and copper during long- patients. Pharmacol Ther 1993;57:291e345.
term parenteral nutrition. J Formosan Med Assoc [71] Herlitz H, Edgar B, Hedner T, et al. Grapefruit juice: A possble
1991;90:1075e80. source of variability in blood concentrations of cyclosprone A.
[58] Milanino R, Frigo A, Bambara L, et al. Copper and zinc status in Nephr Dial Transpl 1993;8:375.
rheumatoid arthritis: Studies of plasma, erythrocytes, and urine [72] Brunner LJ, Munar MY, Vallian J, et al. Interaction between
and their relationship to disease activity markers and phar- cyclosporine and grapefruit juice requires long-term ingestion
macological treatment. Clin Exp Rheumat 1993;11:271e81. in stable renal transplant recipients. Pharmacotherapy
[59] Goldwasser P, Koutelos T, Abraham S, et al. Serum ferritin, 1998;18:23e9.
hematocrit and mean corpuscular volume in hemodialysis. [73] Vicari-Christensen M, Repper S, Basile S, et al. Tacrolimus:
Nephron 1994;67:30e5. review of pharmacokinetics, pharmacodynamics, and pharma-
[60] Schaffer SW, Lombardini JB, Azuma J. Interaction between the cogenetics to facilitate practitioners’ understanding and offer
actions of taurine and angiotensin II. Amino Acids strategies for educating patients and promoting adherence.
2000;18:305e18. Prog Transplant 2009;19:277e84.
[61] Cruz CI, Ruiz-Torres P, del Moral RG, et al. Age-related [74] Melnik G. Pharmacologic aspects of enteral nutrition. In:
progressive renal fibrosis in rats and its prevention with ACE Rombeau J, Coldwell M, editors. Clinical Nutrition: Enteral
inhibitors and taurine. Am J Physiol Renal Physiol 2000;278: and Tube feeding. Philadelphia: W.B. Sauders Company; 1990.
F122e129. p. 472e509.
[62] Franconi F, Bennardini F, Mattana A, et al. Plasma and platelet [75] Behnken I, Gaschott T, Stein J. [Enteral nutrition: drug admin-
taurine are reduced in subjects with insulin-dependent diabetes istration via feeding tube]. Z Gastroenterol 2005;43:1231e41.
mellitus: effects of taurine supplementation. Am J Clin Nutr [76] Au Yeung SC, Ensom MH. Phenytoin and enteral feedings: does
1995;61:1115e9. evidence support an interaction? Ann Pharmacother
[63] Zhao X, Jia J, Lin Y. Taurine content in Chinese food and daily 2000;34:896e905.
intake of Chinese men. Adv Exp Med Biol 1998;442:501e5. [77] Worden J, Wood C, Workman C. Phenytoin and nasogastric
[64] Stangier J, Eriksson BI, Dahl OE, et al. Pharmacokinetic profile feedings. Neurology 1994;34:132.
of the oral direct thrombin inhibitor dabigatran etexilate in [78] Scott D. Addition of potassium supplements to mild-based tube
healthy volunteers and patients undergoing total hip replace- feedings. J Hum Nutr 1980;34:85e90.
ment. J Clin Pharmacol 2005;45:555e63. [79] Valli C, Schultheiss H, Asper R, et al. Interaction of nutrients
[65] Kubitza D, Becka M, Zuehlsdorf M, et al. Effect of food, an with antacids: A complication during enteral tube feeding.
antacid, and the H2 antagonist ranitidine on the absorption Lancet 1986;1:747e8.
of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa [80] Howard P, Hannaman K. Warfarin resistance linked to enteral
inhibitor, in healthy subjects. J Clin Pharmacol 2006;46: nutrition products. J Am Diet Assoc 1985;85:713e5.
549e58. [81] Klang M, Graham D, McLymont V. Warfarin bioavailability
[66] Danovitch G. Immunosuppressive medications and protocols with feeding tubes and enteral formula. JPEN J Parenter Enteral
for kidney transplantation. In: Danovitch G, editor. Handbook Nutr 2010;34:300e4.
of Kidney Transplantation. Boston: Little, Brown and Company; [82] Nimmo W. Drugs, disease and altered gastric emptying. Clin
1992. p. 67e103. Pharmacokinet 1976;1:189e203.
[67] Lindholm A, Henriccson S, Dahlqvist R. The effect of food and [83] Prescott L. Gastric emptying and drug absorption. Br J Clin
bile acid administration on the relative bioavailability of Pharmacol 1974;1:189e90.
cyclosporine. Br J Clin Pharmacol 1990;29:541e8. [84] Couet W, Istin B, Sinuta P, et al. Effect of ponsinomycin on
[68] Kolars J, Awni W, Merion R, et al. First-pass metabolism of cyclosporine pharmacokinetics. Eur J Clin Pharmacol
cyclosporine by the gut. Lancet 1991;338:1488e90. 1990;39:165e7.