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Drug-induced alterations in Mg homoeostasis

Article  in  Clinical Science · July 2012

DOI: 10.1042/CS20120045 · Source: PubMed

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Clinical Science (2012) 123, 1–14 (Printed in Great Britain) doi:10.1042/CS20120045 1

R E V I E W

Drug-induced alterations in
Mg2 + homoeostasis

Anke L. LAMERIS, Leo A. MONNENS, René J. BINDELS and Joost G. J. HOENDEROP

Department of Physiology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands

A B S T R A C T

Clinical Science
Magnesium (Mg2 + ) balance is tightly regulated by the concerted actions of the intestine, bone
and kidneys. This balance can be disturbed by a broad variety of drugs. Diuretics, modulators of
the EGFR (epidermal growth factor receptor), proton pump inhibitors, antimicrobials, calcineurin
inhibitors and cytostatics may all cause hypomagnesaemia, potentially leading to tetany, seizures and
cardiac arrhythmias. Conversely, high doses of Mg2 + salts, frequently administered as an antacid
or a laxative, may lead to hypermagnesaemia causing various cardiovascular and neuromuscular
abnormalities. A better understanding of the molecular mechanisms underlying the adverse effects
of these medications on Mg2 + balance will indicate ways of prevention and treatment of these
adverse effects and could potentially provide more insight into Mg2 + homoeostasis.

INTRODUCTION MAGNESIUM HOMOEOSTASIS

Mg2 + , the second most abundant intracellular divalent
cation, is of central importance for a broad variety of
physiological processes, including intracellular signalling,
neuronal excitability, muscle contraction, bone formation
and enzyme activation. Its overall balance is tightly
regulated by the concerted actions of the intestine,
bones and kidneys, keeping plasma Mg2 + levels within
the range of 0.70 to 1.10 mmol/l. Disturbance of this
balance can have serious consequences. Symptoms of
hypomagnesaemia include tetany, seizures and cardiac
arrhythmias, whereas hypermagnesaemia may cause
various cardiovascular and neuromuscular abnormalities.
Drugs can interfere with Mg2 + homoeostasis in multiple
ways. The aim of the present review is to provide an
overview of the various drugs that are known to influence
Mg2 + homoeostasis and to give some insights into the
underlying physiological mechanisms.
Mg2 + transport can take place via two routes: an
active transcellular pathway or a passive paracellular
route. The transcellular transport of Mg2 + is less well
defined than that of for instance Ca2 + . TRPM (transient
receptor potential melastatin) 6 and 7 cation channels
are thought to be responsible for Mg2 + transport into
the cell. TRPM6 is most abundantly expressed in the
intestine, kidney and lung, whereas TRPM7 is expressed
ubiquitously [1]. Transport of Mg2 + from the tubular or
intestinal lumen into the cell is, therefore, considered to
be mediated predominantly via TRPM6, whereas TRPM7
appears responsible for cellular Mg2 + homoeostasis.
A role for TRPM7 and even for TRPM6–TRPM7
heterotetrameric complexes in the apical transport of
Mg2 + has, however, also been suggested [2,3]. A recent
study by Ryazanova et al. [4] has shown that heterozygote
TRPM7-deficient mice develop hypomagnesaemia due

Key words: drug induction, hypermagnesaemia, hypomagnesaemia, ion channel, kidney, magnesium.
Abbreviations: AGA, aminoglycoside antibiotic; CaSR, Ca2 + -sensing receptor; CLC-Kb, Cl − channel Kb; CsA, cyclosporin A;
DCT, distal convoluted tubule; EGF, epidermal growth factor; EGFR, EGF receptor; NCC, Na + –Cl − co-transporter; NKCC2,
Na + –K + –2Cl − co-transporter; OMIM, Online Mendelian Inheritance in Man; PPI, proton pump inhibitor; PT, proximal tubulus;
PTH, parathyroid hormone; ROMK, renal outer medullary K + channel; TAL, thick ascending limb; TRPM, transient receptor
potential melastatin.
Correspondence: Professor Joost G.J. Hoenderop (email j.hoenderop@fysiol.umcn.nl).


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2 A. L. Lameris and others
to a defect in intestinal absorption of Mg2 + , whereas
renal Mg2 + excretion is appropriately low, indicating
TRPM7 does play an important role in intestinal Mg2 +
homoeostasis. Specific Mg2 + -binding proteins involved
in cytosolic diffusion have not been identified to date. The
calbindin proteins, primarily responsible for cytosolic
Ca2 + transport, have been shown to also bind Mg2 + , but
the physiological relevance of this observation remains
to be determined [5]. The molecular identity of the
basolateral extrusion mechanism for Mg2 + remains to be
defined as well. Extrusion of Mg2 + must occur against an
electrochemical gradient, implicating its dependence on
a primary or secondary active transport process, a Mg2 +
pump or a Na + /Mg2 + exchanger are most frequently
suggested [6,7]. Alternatively, Mg2 + can be absorbed
passively via paracellular transport route. For this latter
process, tight-junction proteins from the claudin family
are important, as they can determine both size and charge
selectivity of the paracellular transport [8].
Intestine
In the intestine, Mg2 + is primarily derived from dietary
sources, such as green leafy vegetables, nuts and whole
grains. Approximately 300 mg of Mg2 + is ingested
on a daily basis, of which 25–75 % is absorbed in
the adult, depending on the availability and needs
of the body [6,9]. When Mg2 + intake is normal, the
transcellular pathway, involving TRPM6, is responsible
for approximately 30 % of absorption, a fraction that
increases when dietary intake is low [10]. Paracellular
transport depends on the transepithelial electrical voltage,
which is approximately 5 mV lumen-positive with respect
to blood. Luminal Mg2 + concentrations range from
1 to 5 mmol/l depending on dietary contents, providing
a transepithelial chemical concentration gradient which
further enhances absorption [10]. Paracellular transport
takes place via tight junctions and is responsible for
approximately 70 % of Mg2 + absorption when luminal
concentrations are high. For the intestine, Mg2 + -specific
paracellular channels have not yet been found; however,
the observation that, for instance, claudin-2 and -12 are
vitamin D-regulated indicates that it is likely that a similar
pathway is involved in intestinal paracellular transport of
divalent cations [11].
Bone
Approximately 50 % of the total Mg2 + body content
resides within the skeleton as part of hydroxyapatite
crystals. The stores in bone serve as a buffer from which
Mg2 + can be released when plasma levels are low and
into which Mg2 + can be stored when circulating Mg2 +
levels are excessive [12]. In animals maintained on a low-
Mg2 + diet, bone Mg2 + content is reduced, as is bone
mineral density [13]. To date, our understanding of the
mechanisms responsible for the mobilization of Mg2 +
into and out of these skeletal stores remains insufficient.

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Kidney
In the kidney, approximately 2.5 g of Mg2 + is filtered by
the glomeruli on a daily basis. Approximately 95 % of this
filtered load is reabsorbed along the different parts of the
nephron via both paracellular and transcellular processes
(Figure 1) [14]. In the PT (proximal tubulus), 10–30 %
is reabsorbed [15,16]. Generally, this occurs via a para-
cellular process, most likely depending on Na + -driven
water transport that increases the intraluminal Mg2 +
concentration of the pro-urine along its way through the
PT; the small lumen-positive potential in the PT also adds
driving force [17–19]. The exact mechanism, however,
remains to be elucidated. Paracellular Mg2 + transport in
the nephron predominates in the TAL (thick ascending
limb) of the nephron, where 40–70 % of the filtered Mg2 +
is reabsorbed [20]. Here, Mg2 + reabsorption is mainly
driven by the lumen-positive transepithelial voltage.
NKCC2 (Na + –K + –2Cl − co-transporter) serves as an
apical entry mechanism for Na + , K + and Cl − . ROMK
(renal outer medullary K + channel) 2 allows for apical
recycling of K + back into the tubular lumen, thereby
generating a lumen-positive voltage of approximately
5–10 mV. Cl − exits via the basolateral membrane via
CLC-Kb (Cl − channel Kb). At the basolateral side, the
Na + /K + -ATPase constitutes the initial driving force
for Na + transport in the TAL. Here, the paracellular
Mg2 + reabsorption depends on the lumen-positive
transepithelial voltage and is facilitated by claudin-16 and
-19, which are two tight-junction proteins that operate
together to form a cation-permeable channel [21]. At the
basolateral side, CaSR (Ca2 + -sensing receptor) can mod-
ulate transport in response to changes in concentration of
extracellular cations, reducing transport upon stimulation
[22]. In the DCT (distal convoluted tubule) the final 5–
10 % of Mg2 + is reabsorbed in an active transcellular
manner [23]. The tubular epithelium in this part of the
nephron consists of a high-resistance epithelium with a
lumen-negative voltage of approximately − 5 mV. Apical
reabsorption occurs via TRPM6, which can be stimulated
via the basolateral EGFR [EGF (epidermal growth factor)
receptor] [24]. Kv1.1, an apically located K + channel,
establishes a favourable luminal membrane potential
facilitating an increase in the driving force for Mg2 +
reabsorption via TRPM6 [25]. The Na + /K + -ATPase at
the basolateral membrane provides the Na + gradient that
is utilized by the apical NCC (Na + –Cl − co-transporter)
to transport NaCl into the cell, while K + that enters at
the basolateral side in this process is recycled via Kir4.1.
The Mg2 + reabsorption in the DCT defines the final
urinary Mg2 + excretion, as there is no significant
reabsorption of Mg2 + beyond the DCT.
HYPOMAGNESAEMIA
Hypomagnesaemia is defined as a serum Mg2 +
concentration of less than 0.70 mmol/l. Muscle cramps,
 Drug-induced alterations in Mg2 + homoeostasis 3

Figure 1 Schematic representation of the nephron and electrolyte handling in the TAL of Henlē and DCT
(A) Approximately 95 % of the Mg2 + filtered in the glomerulus is reabsorbed from the pro-urine along the different segments of the nephron. Of this filtered Mg2+
load, 10–30 % is reabsorbed in the PT, followed by an additional 40–70 % in the TAL. The DCT is responsible for the transport of the final 5–10 % of Mg2 + back
into the blood. CNT, connecting tubule; TDL, thin desending limb. (B) In the TAL, NKCC2 allows apical entry of Na + , K + and Cl − . ROMK2 recycles K + back into
the tubular lumen. Cl − exits via the basolateral membrane via CLC-Kb. At the basolateral side, the Na + /K + -ATPase constitutes the initial driving force for Na +
transport in the TAL. Paracellular Mg2 + absorption is facilitated by claudin-16 and claudin-19 (CLDN16/19). CaSR will reduce the absorption upon stimulation by
extracellular cations. (C) In the DCT, Mg2 + absorption via TRPM6 depends on the membrane potential, which is set by Kv1.1 and can be stimulated via EGFR. The
Na + /K + -ATPase at the basolateral membrane provides an Na + gradient that is used by NCC on the apical cell membrane. K + that enters the cell in this process
is recycled via Kir4.1.

tetany and muscular weakness are the main complaints
of hypomagnesaemic patients [26]. Cardiovascular
abnormalities, such as arrhythmias and convulsions, have
also been described. Hypomagnesaemia is, however,
often associated with multiple biochemical abnormalities
such as hypokalaemia and hypocalcaemia. It is, therefore,
difficult to ascribe specific clinical manifestations solely
to hypomagnesaemia. In this regard, important lessons
can be learned from patients with isolated forms of
hypomagnesaemia, such as isolated dominant [OMIM
(Online Mendelian Inheritance in Man) #154020,
#176260 and #613882] and isolated recessive (OMIM
#611718) hypomagnesaemia. It must, however, be noted
that these cases reflect only the chronically Mg2 +
-depleted state.
Isolated dominant hypomagnesaemia can be caused
by mutations in the FXYD2 gene, encoding the γ -
subunit of the Na + /K + -ATPase. The two index patients
described, with serum Mg2 + levels of approximately 0.4
mmol/l, suffered from generalized convulsions and severe
mental retardation was present in one of the patients.
Remarkably, other family members with low serum
Mg2 + levels (0.32–0.65 mmol/l) showed no symptoms
of hypomagnesaemia [27–29]. In isolated autosomal-
dominant hypomagnesaemia due to mutations in KCNA1
(encoding Kv1.1), serum Mg2 + levels <0.40 mmol/l
were found in an index patient suffering from recurrent
muscle cramps, tetanic episodes, tremor and muscular
weakness. Serum Mg2 + values of 0.37 and 0.25 mmol/l
with normal serum Ca2 + and K + values were reported
in affected family members during severe attacks of
cramps and tetany [25]. In another form of dominant
hypomagnesaemia caused by mutations in the CNNM2
gene (encoding cyclin M2), the index patient had a
serum Mg2 + level of 0.36 mmol/l and suffered from
weakness of the limbs, vertigo and headaches, but no
other electrolyte abnormalities were described [30,31].
Recessive hypomagnesaemia resulting from mutations in
the EGF gene also leads to isolated hypomagnesaemia.
Two sisters were described with generalized seizures
during infancy, and were found to have serum Mg2 +
levels of 0.53–0.66 mmol/l with no other clear clinical
symptoms [32].
Chronic depletion of Mg2 + , as reflected by the
low serum Mg2 + levels, generally becomes clinically
evident in patients with serum Mg2 + concentrations


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4 A. L. Lameris and others
of <0.40 mmol/l. As mentioned above, hypocalcaemia
(muscle cramps and tetany) and hypokalaemia (muscle
weakness), when occurring secondary to hypomag-
nesaemia, will contribute to the clinical phenotype.
Hypokalaemia associated with hypomagnesaemia is
often refractory to treatment by K + and can only
be properly corrected when Mg2 + is co-administered.
The decreased intracellular Mg2 + concentration resulting
from Mg2 + deficiency, releases the Mg2 + -mediated
inhibition of ROMKs, thereby increasing K + excretion
[33]. Hypocalcaemia secondary to hypomagnesaemia has
been hypothesized to originate from inappropriately low
PTH (parathyroid hormone) secretion, the release of
which depends on an intracellular signalling cascade that
requires Mg2 + . In addition, the responsiveness of target
organs to PTH stimulation seems to be reduced [34,35].
Hypocalcaemia secondary to hypomagnesaemia with low
PTH secretion is mostly seen when serum Mg2 + levels
are extremely low [36]. Treatment is only successful
when hypomagnesaemia is addressed together with the
hypocalcaemia, as Ca2 + supplementation alone will not
suffice [34].
Assessment of Mg2 + status
In clinical practice total serum Mg2 + is most commonly
used to assess the Mg2 + status in patients. This
parameter does not necessarily reflect the true total
body Mg2 + content, as normal serum Mg2 + levels
may be present despite intracellular depletion. Using
ion-selective electrodes it is possible to measure solely
ionized Mg2 + . Some studies indicate that ionized Mg2 +
is a better representative of the Mg2 + status compared
with total serum Mg2 + , whereas others find both
parameters equally representative. The Mg2 + content
of erythrocytes, leucocytes and platelets has also been
suggested as potential biomarkers for the assessment of
Mg2 + status. However, their usefulness and reliability are
currently under debate. Alternatives such as measuring
Mg2 + content of bone, teeth, muscle, hair or nails are
either too invasive, too laborious or not reliable to use in
daily clinical practice [37]. An easy non-invasive method
is to analyse urinary Mg2 + excretion. As renal Mg2 +
excretion will decrease in response to deficiency, this is
an important parameter during assessment of Mg2 + status
[37].
The Mg2 + status can also be evaluated in balance
studies by determining Mg2 + faecal as well as renal
excretion after oral loading or intravenous infusion.
Since the results of these tests are partly dependent
on the renal function, the risk of false-negative and
false-positive outcomes should be taken into account.
Owing to these and other limitations, balance studies
are not frequently performed [38]. For some minerals,
radioactive isotopes can be used to assess the mineral
balance. For safety reasons radioactive isotopes are not
often employed for balance studies in humans, but in

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animal models they can be useful and are, therefore,
frequently applied. The use of radioactive Mg2 + isotopes
for balance studies is unfortunately limited by the short
Mg2 + isotope half-lives, which range from 21 h to just
milliseconds. Stable Mg2 + isotopes such as 25 Mg or 26 Mg
can be distinguished from 24 Mg using inductively coupled
plasma mass spectrometry. Owing to their relatively high
natural abundance, high doses of the enriched isotopes
are required for analytical precision, making this type of
experiments not only technically demanding, but also
relatively expensive [39].
In conclusion, a simple, rapid and accurate test
to assess total body Mg2 + status is lacking. Until
adequate alternatives become available, the combined
determination of serum Mg2 + and urinary Mg2 +
excretion remains the only practical test to assess
Mg2 + status.
Treatment of hypomagnesaemia
The route of administration of Mg2 + supplements
depends on the severity of clinical findings and the origin
of the hypomagnesaemia. Patients can be treated with
oral supplements, with intramuscular injections or
with intravenous infusions [40]. Intravenous adminis-
tration is the most effective in restoring serum Mg2 +
to normal levels and is, therefore, the best treatment in
cases of severe hypomagnesaemia. The disadvantage is
that patients have to visit the hospital on a regular basis if
frequent treatment is required. Oral supplements do not
require hospital visits; however, not all patients tolerate
oral supplementation of Mg2 + due to their cathartic
effect at higher dosages. Solubility and bioavailability
vary greatly between various Mg2 + supplements. In
general, organic Mg2 + salts have a higher solubility
and bioavailability compared with inorganic Mg2 + salts,
making them more suitable for oral Mg2 + replacement
therapy. It should be noted that, in cases of severe
hypomagnesaemia or Mg2 + deficiency due to intestinal
malabsorption, oral Mg2 + supplements may not be
sufficient to restore serum Mg2 + levels to normal.
DRUG-INDUCED HYPOMAGNESAEMIA
A summary of the drugs described below is provided in
Table 1 and Figure 2.
Diuretics
Diuretics increase urinary output and are widely used in
the treatment of hypertension, heart failure and kidney
diseases. They may cause hypermagnesuria, leading
to possible hypomagnesaemia and Mg2 + depletion.
Three types of diuretics are known to influence Mg2 +
homoeostasis, namely osmotic diuretics, loop diuretics
and thiazide-type diuretics.
 Drug-induced alterations in Mg2 + homoeostasis 5

Table 1 Drug-induced changes in Mg2 + homoeostasis

Hypomagnesaemia Hypermagnesaemia

Drug/compound Reference(s) Drug/compound References

Diuretics Epsom salt poisoning [103,106–108]

Osmotic diuretics [41] Overdose using Mg2 + as a cathartic [108,110,111]
Loop diuretics [41,42] Antacids [112–115]
Thiazide-type diuretics [43–49] Laxative abuse [119,121,122]
EGFR modulators Enemas containing Mg2 + [107,123,124]
Cetuximab [32,50–55]
Erlotinib [56]
PPIs [57–65]
Antimicrobials
AGAs [66–73]
Pentamidine [74–78]
Sirolimus [52,79,80]
Amphotericin B [81,82]
Foscarnet [83,84b]
Calcineurin inhibitors
CsA [86–91]
FK506 [92–95]
Cisplatin/carboplatin [96–101]

Figure 2 Overview of drugs causing hypomagnesaemia

Overview of the six classes of drugs described causing hypomagnesaemia. Effects of individual drugs on key players in Mg2 + homoeostasis in cells of the TAL and
DCT are displayed. Pentamidine and cisplatin are not know to have an effect on specific proteins involved in Mg2 + homoeostasis, but have been shown to be toxic
to/accumulate in DCT cells respectively.


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6 A. L. Lameris and others
Osmotic diuretics
Osmotic diuretics (such as mannitol) are solutes that are
not absorbed or only partly absorbed from the renal
tubular lumen. They diminish salt and water reabsorption
by increasing the flow rate thereby reducing, among
others, serum Mg2 + levels [41].
Loop diuretics
Loop diuretics (such as furosemide, bumetanide,
torsemide and ethacrynic acid) act in the TAL by
competing for the Cl − site on NKCC2. Inhibition
of apical Cl − reabsorption and diminished basolateral
Cl − efflux lead to a loss of lumen-positive potential,
thus resulting in a diminished driving force for
paracellular cation reabsorption [42]. Therefore the use
of loop diuretics may lead to renal Mg2 + wasting and
hypomagnesaemia due to reduced paracellular Mg2 +
reabsorption via claudin-16 and -19 [41].
Thiazide-type diuretics
Thiazide-type diuretics comprise a class of diuretics de-
rived from benzothiadiazine, but also drugs with similar
action that do not have the thiazide chemical structure
such as chlortalidone and metolazone. Thiazides enhance
renal Na + excretion by inhibiting NCC in the DCT cells
[43]. Thiazide treatment leads to hypomagnesaemia as
well as hypocalciuria [44,45]. In contrast with the effects
of thiazide-type diuretics on Ca2 + balance, which seem
to differ in short- and long-term treatment, the effect of
thiazides on Mg2 + reabsorption only becomes apparent
upon chronic treatment [46]. Hypomagnesaemia has been
suggested to result from K + deficiency, increased passive
Mg2 + secretion or decreased active Mg2 + reabsorption
in the DCT [47–49]. Chronic administration of thiazides
enhances renal Mg2 + excretion and specifically reduced
renal expression levels of TRPM6 in a mouse model. In
the same study, it was shown that TRPM6 expression
levels were severely decreased in NCC-knockout mice.
Therefore the pathogenesis of hypomagnesaemia in
chronic thiazide treatment appears to result from specific
TRPM6 down-regulation in the DCT [46].
EGFR modulators
EGF is an important growth factor that is synthesized
as a pre-proprotein, which is cleaved and subsequently
processed into the mature EGF [50–51a]. EGF acts
by binding with high affinity to EGFR, which is
generally localized at the basolateral cell surface, thereby
stimulating the intrinsic protein tyrosine kinase activity
of the receptor and activating intracellular signalling
cascades. EGFR is overexpressed in a broad variety of
tumour cells, making it an effective target for anticancer
treatments. In the nephron, EGFR is expressed along the
TAL and DCT [32].
In 2007, Groenestege et al. [32] presented two
sisters with low serum Mg2 + concentrations and an

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inappropriately high fractional excretion of Mg2 + . They
identified a mutation in the pro-EGF gene that, upon
closer investigation, was found to cause a defect in the
sorting of the pro-EGF, resulting in impaired basolateral
sorting. Owing to the resulting lack of release of the
hormone on the basolateral side, the EGFR in the
DCT could not be stimulated. This study demonstrated
that TRPM6 activity was increased upon binding of
EGF to EGFR, making EGF the first magnesiotropic
hormone. The increased activity results from an
increase in the mobility and cell-surface expression
of TRPM6 [52]. These findings matched perfectly
with earlier observations that certain EGFR-targeting
chemotherapeutic agents cause hypomagnesaemia. There
are actually two main classes of anticancer agents that
affect the EGFR: those targeting the extracellular ligand-
binding domain (such as cetuximab and panitumumab)
and drugs that block the intracellular tyrosine kinase
domain (such as erlotinib and gefitinib).
Cetuximab (erbitux)
Cetuximab is a chimaeric (mouse/human) monoclonal
antibody, which functions as an EGFR antagonist by
preventing the binding of EGF and triggering the
internalization of the receptor, consequently leading
to inhibition of EGFR activation. Approximately
1.5 years after its release by the U.S. FDA (Food
and Drug Administration) in 2004, a warning was
released concerning the relationship between severe
hypomagnesaemia and cetuximab treatment. Several
groups have performed retrospective studies to determine
the incidence of cetuximab-induced hypomagnesaemia
[53,54]. These studies are, however, hindered by the
fact that Mg2 + levels are not commonly determined
in all patients. In a prospective study, it was shown
that in most patients serum Mg2 + concentrations during
EGFR-targeting treatment had decreased compared with
baseline measurements [55]. In total, 54 % of the treated
patients developed hypomagnesaemia (defined as serum
Mg2 + levels <0.65 mmol/l), and in 6 % of all patients
hypomagnesaemia was severe (serum Mg2 + levels <0.4
mmol/l). Clinically significant hypocalcaemia was rare
and not progressive upon treatment. Careful monitoring
of serum Mg2 + levels is, therefore, essential during
treatment.
Erlotinib (tarceva)
Erlotinib is a tyrosine kinase inhibitor that acts
on EGFR. It binds in a reversible fashion to the
ATP-binding site of the receptor. For the signal to
be transmitted, two members of the EGFR family
need to dimerize. The two halves of the dimerized
EGFR then autophosphorylate each other using one
ATP molecule. The autophosphorylation causes a
conformational change in the intracellular structure of
EGFR, which is essential for the activation of the

intracellular signalling cascade that takes place upon
binding of EGF to EGFR. By inhibiting the binding
of ATP, autophosphorylation is not possible and the
signal is blocked. To date, reports on erlotinib-induced
hypomagnesaemia in patients are lacking. A recent study
by Dimke et al. [56] determined the effect of erlotinib on
Mg2 + homoeostasis. In vivo studies showed a small, but
significant, effect on serum Mg2 + levels; furthermore,
mice failed to decrease renal fractional excretion of
Mg2 + in reaction to reduced Mg2 + levels. Although
TRPM6 expression was lowered at the mRNA level, no
changes were found at the protein level. Erlotinib failed
to inhibit EGF-induced changes in TRPM6 activity at
physiological concentrations [56]. Taken together, these
observations indicate that the effect of erlotinib on Mg2 +
homoeostasis is minimal. Nevertheless, in the case of
erlotinib treatment in patients predisposed to developing
hypomagnesaemia, extra caution is warranted.
The dissimilarity between anti-EGFR antibodies and
EGFR tyrosine kinase inhibitors on Mg2 + handling is
still not fully understood; most probably differences
in the bioavailability of erlotinib and cetuximab play
a decisive role in the aetiology of EGFR modulator-
induced hypomagnesaemia [56].
PPIs (proton pump inhibitors)
PPIs belong to the most widely prescribed classes of
drugs in the world. In 2006, two cases of PPI-induced
hypomagnesaemia were published by Epstein et al. [57].
Since then, several groups have described similar findings
in patients using PPIs [58–62]. The exact prevalence
remains unknown; however, the growing number of case
reports indicates that these patients might represent the
‘tip of an iceberg’.
Patients generally suffer from hypomagnesaemia and
often have secondary hypocalcaemia and hypokalaemia.
Long-term use seems to play a role, as all patients
were using PPIs for more then 1 year. Remarkably,
patients recover relatively quickly upon discontinuation
and relapse within days when medication is restarted.
This could indicate that PPIs might have a relatively
subtle effect on Mg2 + homoeostasis, which only becomes
overt when Mg2 + stores are completely depleted.
Indeed, Mg2 + retention upon intravenous infusion is
high, suggesting severe depletion of the body’s Mg2 +
stores. Urinary Mg2 + excretion is low, indicating intact
renal function. Taken together, these findings point
towards an intestinal abnormality as the most likely
problem underlying PPI-induced hypomagnesaemia.
Studies examining the effect of PPIs on the intestinal
absorption of various salts have not identified differences
in the absorption of Mg2 + [63,64]. All studies were,
however, performed after short-term PPI use and were
based on faecal excretion analysis; a long-term effect or
a subtle effect for which this technique is not sensitive
enough and can, therefore, not be excluded.
Drug-induced alterations in Mg2 + homoeostasis 7
Several explanations have been suggested in the pub-
lished case reports. First, Mg2 + absorption might depend
on the stomach’s acidity for solubilization. Achlorhydria
caused by PPIs could, therefore, reduce Mg2 +
availability for absorption, resulting in diminished Mg2 +
absorbed in the intestine. A second explanation would
be an increase in intestinal Mg2 + loss via secretion;
considerable amounts of Mg2 + can be excreted in the
intestine, and thus a shift in the balance between Mg2 +
absorption and secretion in the intestine could result in
net Mg2 + loss. Thirdly, active transcellular or passive
paracellular Mg2 + absorption could be impaired. TRPM6
activity is positively regulated by extracellular protons,
and an inhibitory effect of PPIs on the colonic H + /K + -
ATPase (a homologue of the gastric H + /K + -ATPase that
is inhibited by PPIs) could reduce TRPM6 activity due to
a decreased level of excreted protons. Recently, Thongon
and Krishnamra [65] have shown that omeprazole
treatment of Caco-2 monolayers can decrease paracellular
cation permeability leading to suppression of passive
Mg2 + absorption. A clear molecular explanation for this
observation is still lacking.
More studies need to be performed to determine
the incidence of PPI-induced hypomagnesaemia and
to unravel the underlying mechanisms. Meanwhile,
physicians should be aware of this serious side effect
of PPIs. Patients suffering from hypomagnesaemia due
to PPIs can be treated with supplements or switched to a
histamine H2 receptor antagonist.
Antimicrobials
AGAs (aminoglycoside antibiotics)
AGAs such as gentamycin, tobramycin and amikacin are
widely used in the treatment of severe bacterial infections
of the abdomen and urinary tract because of their high
efficacy. Side effects can, however, be serious, with
nephrotoxicity and ototoxicity occurring in up to 35 %
of the treated patients. As many as 25 % of the patients
will develop hypomagnesaemia due to renal Mg2 + loss
[66]. The effect of AGAs on Mg2 + balance is not directly
dose-dependent, but seems to be related to the cumulative
doses of AGAs received by the patient during treatment.
Onset of hypomagnesaemia can take up to 2 weeks and
can persist after cessation of AGA treatment for several
months [67]. Hypermagnesuria is generally accompanied
by hypercalciuria, which suggests that AGAs exert an
effect on renal solute transport in those tubular segments
where both Ca2 + and Mg2 + are reabsorbed, i.e. the TAL
and DCT. AGAs do not accumulate in the more distal
parts of the nephron, but up to 10 % of the administered
dose accumulates in the renal cortex, especially in the
PT cells, where intracellular accumulation of AGAs
leads to damage as indicated by the increase in specific
biomarkers [68,69]. Animal experiments have shown
renal Mg2 + wasting in the absence of renal failure

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8 A. L. Lameris and others
or tubular morphology abnormalities [70]. In a recent
study, Tzovaras et al. [71] found no correlation between
changes in Mg2 + and Ca2 + excretion with alterations in
urine lactate, alanine or hippurate used as markers for
nephrotoxicity. Together, these findings indicate that the
proximal and distal renal tubular dysfunction as a result of
AGA treatment is caused by two independent processes.
AGAs can function as polyvalent cations and can thus
stimulate the CaSR [72,73]. Activation of the CaSR by
polyvalent cations could inhibit the passive reabsorption
of Ca2 + and Mg2 + in the TAL and active absorption
in the DCT. Indeed, Sassen et al. [70] have shown
a decreased expression of NKCC2 and an increased
expression of CaSR in the TAL of gentamycin-treated
rats. The reduced NKCC2 expression would result in a
decrease in the lumen-positive membrane voltage and is,
therefore, likely to contribute to the increased urinary
Ca2 + and Mg2 + excretion resembling the response to
furosemide treatment.
Pentamidine
Pentamidine is an antimicrobial used in the prevention
or treatment of pneumocystic pneumonia in immuno-
compromised patients. Treatment with pentamidine can
lead to severe symptomatic hypomagnesaemia secondary
to renal Mg2 + wasting, typically in association with
hypocalcaemia, which has been observed to continue
for up to 2 months after cessation of pentamidine
treatment [74–76]. The exact molecular mechanism
underlying this renal Mg2 + leakage is unknown; however,
autopsy studies in AIDS patients has shown pentamidine
accumulation in renal tissue from 1 day to 1 year after
the completion of therapy [77,78]. In addition, the
epithelium of the DCT was degenerated, suggesting that
pentamidine-induced hypomagnesaemia might be the
result of diminished active Mg2 + reabsorption in
the kidney.
Rapamycin (sirolimus)
Rapamycin is a macrolide antibiotic derived from fungus.
It was the first inhibitor of the mTOR (mammalian
target of rapamycin) pathway approved by the FDA
and it is frequently used to prevent post-transplant
organ rejection. Treatment with rapamycin is associated
with increased renal Mg2 + excretion resulting in
hypomagnesaemia [79]. da Silva et al. [80] showed a
marked decrease in both plasma K + and Mg2 + in
sirolimus-treated rats. In addition, increased urinary
excretion of Na + , K + and Mg2 + was found, whereas the
glomerular filtration rate remained unchanged. Sirolimus
treatment reduced the expression of NKCC2 and AQP2
(aquaporin 2), whereas TRPM6 expression was increased,
which could represent either a direct stimulatory effect
of sirolimus or a compensatory response [80]. Recently,
Ikari et al. [52] demonstrated in an in vitro study
that rapamycin inhibits the EGF-mediated increase

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in TRPM6 expression by reducing mRNA stability.
Clinical implications of these findings remain to be
determined; however, they indicate hypomagnesaemia
due to rapamycin treatment is the result of a defect in
Mg2 + absorption by DCT cells.
Amphotericin B
Amphotericin B is an antifungal drug that is mainly
used to treat various systemic fungal infections in
immunocompromised patients or for parasitic protozoan
infections. Amphotericin B causes renal injury leading
to renal insufficiency, urinary K + wasting and
hypokalaemia, Mg2 + wasting and hypomagnesaemia,
metabolic acidaemia due to distal renal tubular acidosis,
and polyuria [81]. Barton et al. [82] found reduced serum
Mg2 + levels and an increase in renal Mg2 + excretion upon
treatment with amphotericin B. They also showed that
the effect is reversible and Mg2 + homoeostasis returns to
normal baseline levels upon discontinuation of treatment
[82]. To date, no molecular data explaining amphotericin
B-induced hypomagnesaemia are available.
Foscarnet (trisodium phosphonoformate hexahydrate)
Foscarnet is a pyrophosphate analogue that inhibits many
viral DNA polymerases [83]. It is used to treat cytomeg-
alovirus and acyclovir-resistant mucocutaneous herpes
simplex virus disease in immunocompromised patients.
Its side effects include hypomagnesaemia, hypocalcaemia
and hypokalaemia [84]. Being a pyrophosphate analogue,
foscarnet is a potent chelator of divalent cations. Thus
complexes readily form with Mg2 + and Ca2 + , and a
linear relationship exists between serum divalent ions and
circulating plasma foscarnet concentrations [84a,84b].
This suggests that foscarnet-induced hypomagnesaemia
is solely the result of the physical interaction between
foscarnet and Mg2 + . It would be interesting, however,
to investigate whether adaptational changes occur in
expression of, for example, TRPM6.
Calcineurin inhibitors
Calcineurin inhibitors such as CsA (cyclosporin A;
ciclosporin) and FK506 are immunosuppressant drugs
that are widely prescribed in post-transplantation
immunosuppression and for numerous immunological
disorders. Calcineurin inhibitors are known to cause
renal injury, hypertension and tubular dysfunction
with disturbances of mineral metabolism. Both drugs
commonly lead to hypomagnesaemia due to renal Mg2 +
wasting, hypercalciuria and hypokalaemia [85].
CsA
CsA is known to cause nephrotoxicity in a dose-
dependent and reversible manner [86–88]. CsA treatment
also frequently results in a disruption of mineral
homoeostasis, with 10–36 % of CsA-treated patients
developing hypomagnesaemia [88,89]. In vitro, CsA

significantly reduces the expression of claudin-16 and
TRPM6, but not TRPM7, at both the mRNA and protein
levels; for TRPM6, the decreased expression is mediated
by the inhibition of c-Fos transcription [89,90]. A recent
study has described an increase in the fractional excretion
of Mg2 + in rats as a result of CsA treatment [91].
The study also showed a reduction in the expression
levels of TRPM6, TRPM7, NCC and EGF, whereas
reduced expression of EGFR or claudin-16 was not found
[91]. Together, these findings indicate CsA reduces renal
Mg2 + reabsorption in the DCT, possibly via the down-
regulation of TRPM6.
FK506 (tacrolimus)
FK506 treatment is frequently associated with an
inappropriately high fractional excretion of Mg2 + and
Ca2 + [92]. Nijenhuis et al. [93] found decreased renal
levels of TRPV5 (transient receptor potential vanilloid
5), calbindin-D28K and TRPM6 mRNA expression in
the kidneys of rats treated with FK506. The expression
of specific DCT markers was unaltered, excluding the
possibility that the reduction in Mg2 + reabsorption is
the result of a general toxic effect of FK506 on DCT
cells [93]. It has been shown that FK506 treatment
results in decreased intracellular Mg2 + concentrations in
human osteoblast cells, suggesting that changes in Mg2 +
homoeostasis might also be involved in the reduced bone
mineralization caused by FK506 treatment [94]. A recent
study has shown that FK506 can suppress VDR (vitamin
D receptor) expression; the renal loss of both Mg2 +
and Ca2 + occurring despite increased vitamin D
levels suggests a possible aetiological role of
vitamin D resistance [95]. Further studies are needed to
unravel the underlying molecular mechanisms.
Cisplatin
Cisplatin (cis-diammine dichloroplatinum) is widely used
to treat various solid tumours. Among the various
side effects, nephrotoxicity is generally considered the
most important since it is the main dose-limiting factor
in the treatment of patients [96]. Hypomagnesaemia
due to renal Mg2 + wasting is common in cisplatin-
treated patients; an additional effect of reduced intestinal
absorption of Mg2 + cannot be excluded as the
absorption of several electrolytes has been shown to
be reduced by cisplatin treatment [97]. The incidence
of Mg2 + deficiency is >30 % and is augmented with
increased dosage or prolonged duration of treatment
[98]. Interestingly, hypomagnesaemia caused by cisplatin
treatment seems to be Mg2 + -specific, with hypocalcaemia
and hypokalaemia only occurring with prolonged and
severe Mg2 + deficiency [97]. Cisplatin predominantly
accumulates in the PT and DCT, but effects of cisplatin
may persist long after all inorganic platinum has
disappeared from renal tissue [99,100]. In addition,
hypomagnesaemia and cisplatin accumulation appear to
Drug-induced alterations in Mg2 + homoeostasis 9
Table 2 Symptoms of hypermagnesaemia
Serum Mg2 + level (mmol/l) Symptoms
0.7–1.1 None; normal serum level
1.1–2.0 Asymptomatic
2.0–3.0 Nausea, vomiting, cutanous vasodilation,
headaches, hyporeflexia and lethargy
3.0–5.0 Unresponsiveness, loss of deep tendon
reflexes, electrocardiographic changes,
such as prolongation of QRS, PR and QT
intervals, bradycardia and hypotension
>5.0 Complete heart block, respiratory paralysis,
coma and shock
>8.0 Asystole and death
enhance each other in a vicious circle in which cisplatin
treatment causes renal Mg2 + loss and the resulting
hypomagnesaemia stimulates cisplatin accumulation in
the kidney [101].
HYPERMAGNESAEMIA
Hypermagnesaemia causes a broad variety of symptoms
depending on the serum Mg2 + levels (Table 2)
[26,102,103]. In the case of a relatively mild degree of
hypermagnesaemia, patients may suffer from nausea,
vomiting and flushing. Within the asymptomatic
and mildly symptomatic stages of hypermagnesaemia
(between 1.1 and 3.0 mmol/l), there is also the therapeutic
range in which hypermagnesaemia can be used to
control convulsions [104]. When the plasma Mg2 +
levels increase further, symptoms become increasingly
dangerous, eventually leading to a comatose state and/or
asystole. As the renal response to high Mg2 + levels
is extremely efficient, hypermagnesaemia is relatively
rare and primarily observed in patients with renal
insufficiency. It has, however, also been detected in
individuals with normal renal function as a result of
exogenous administration via oral, intravenous or rectal
routes [105]. A summary of the effects of the compounds
described below is provided in Table 1.
Epsom salt poisoning
The heptahydrate of MgSO4 , also known as Epsom
salt, is often used as bath salt in flotation therapy,
but it is also applied as a home remedy for numerous
ailments, including abdominal pain, constipation, sprains
and muscle strains. Accidental excessive ingestion can
lead to severe hypermagnesaemia. Several fatal or almost
fatal cases of hypermagnesaemia due to Epsom salt
poisoning have been reported in which patients used
Epsom salt gargles, Epsom salt enemas or simply ingested
several tablespoons of Epsom salt in an attempt to heal
various ailments [103,106–108].

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10 A. L. Lameris and others
Overdose using Mg2 + as a cathartic
Gastrointestinal decontamination after a toxic ingestion
typically involves three actions, all aiming to minimize
absorption of ingested poisons: gastric emptying by
aspiration and lavage, administration of an absorbing
agent such as active charcoal to bind the toxic agent, and
catharsis [109]. Cathartics decrease absorption of toxic
substances by accelerating the transport of both the toxic
substance and the charcoal–substance complex through
the intestine, thereby reducing the bodies exposure
time to the toxins. Mg3 (C6 H5 O7 )2 (magnesium citrate)
is often used as a cathartic after oral poisoning or
overdosing, and is considered safe in patients with
normal renal function. Upon multiple doses, however,
this treatment can lead to severe hypermagnesaemia
[108,110,111]. Careful monitoring of serum Mg2 + levels
during treatment of patients with multiple doses of
Mg3 (C6 H5 O7 )2 is, therefore, strongly advised.
Antacids
Many types of antacids contain Mg(OH)2 . Available as
over-the-counter drugs, Mg2 + -based antacids such as
milk of magnesia are generally considered to be safe.
The Mg2 + load posed by these drugs can indeed, under
normal circumstances, easily be excreted via the kidneys.
However, when renal function is compromised or when
extreme amounts are ingested, hypermagnesaemia may
develop [112–115].
Laxative abuse
Various compounds containing Mg2 + [such as
Mg3 (C6 H5 O7 )2 , Mg(OH)2 and MgSO4 ] can be used
as laxatives. They increase the faecal water content,
leading to softer stools and eventually diarrhoea. This
has long-been ascribed to the increased osmotic pressure
in the colon due to large amounts of unabsorbed Mg2 +
and SO4 2 − Two recent studies, however, have found
that the Mg2 + -induced diarrhoea is not solely the result
of increased osmotic pressure. Upon treatment with
Mg2 + salts, aquaporin-3 expression in the Caco-2 cell
line increases in a Mg2 + -specific manner, inducing an
increase in water permeability [116,117]. This increase in
aquaporin-3 expression was also observed in rats [118].
High dosages and impaired renal function increase the
risk of hypermagnesaemia due to the use of laxatives
[119,120]. In addition in children and laxative abusers,
such as for instance patients with eating disorders,
laxatives can lead to hypermagnesaemia [119,121,122].
Enemas
In the past, Mg2 + -containing enemas were applied in
cases of obstipation. We now know that in the large
intestine substantial quantities of Mg2 + can be absorbed,
explaining the numerous cases of fatal hypermagnesaemia
occurring even in patients with normal renal function

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[107,123,124]. As several safe alternatives are available
nowadays, the use of Mg2 + -containing enemas is no
longer recommended.
Treatment of hypermagnesaemia
Treatment of hypermagnesaemia should primarily be
aimed at lowering plasma Mg2 + levels. However,
when serious complications of Mg2 + intoxication are
present, intravenous administration of low doses of
Ca2 + may quickly reduce the severity of symptoms
due to the antagonistic effect of Ca2 + on Mg2 + . It is
therefore the advised initial treatment in the case of life-
threatening situations. In addition, haemodialysis may
be used to quickly reduce serum Mg2 + levels in severe
cases [125,126]. Next, oral intake and/or intravenous
administration of Mg2 + salts should be discontinued
immediately to avoid further intoxication. Subsequently,
renal Mg2 + excretion could be stimulated by intravenous
administration of furosemide and saline to ensure high
urine output and to prevent volume depletion [127].
SUMMARY
Tightly controlled Mg2 + balance is essential for ample
physiological processes and consequently disturbance
of this balance can have serious clinical consequences.
There is a large variety of drugs that influence
Mg2 + homoeostasis in various ways, causing either
hypo- or hyper-magnesaemia. A better understanding
of the mechanisms that are underlying the drug-
induced changes in Mg2 + homoeostasis could allow the
development of drugs with less side effects and thus
better patient care. The discovery of novel key players
in Mg2 + homoeostasis could help to further elucidate the
molecular pathways involved in (re)absorption of Mg2 +
as well as its regulation.
ACKNOWLEDGEMENT
We thank Bob Glaudemans for his help in preparation of
the Figures.
FUNDING
Our work was supported by the Netherlands Organiza-
tion for Scientific Research [grant numbers TOP ZonMw
91208026, NWO-ALW 818.02.001], a EURYI award
from the European Science Foundation and the Dutch
Kidney Foundation [grant number C08.2252].
REFERENCES
1 Groenestege, W. M., Hoenderop, J. G., van den Heuvel,
L., Knoers, N. and Bindels, R. J. (2006) The epithelial
Mg2 + channel transient receptor potential melastatin 6 is
regulated by dietary Mg2 + content and estrogens. J. Am.
Soc. Nephrol. 17, 1035–1043

2 Chubanov, V., Waldegger, S., Mederos y Schnitzler, M.,
Vitzthum, H., Sassen, M. C., Seyberth, H. W., Konrad, M.
and Gudermann, T. (2004) Disruption of TRPM6/
TRPM7 complex formation by a mutation in the TRPM6
gene causes hypomagnesemia with secondary
hypocalcemia. Proc. Natl. Acad. Sci. U.S. A. 101,
2894–2899
3 Chubanov, V., Schlingmann, K. P., Waring, J., Heinzinger,
J., Kaske, S., Waldegger, S., Mederos y Schnitzler, M. and
Gudermann, T. (2007) Hypomagnesemia with secondary
hypocalcemia due to a missense mutation in the putative
pore-forming region of TRPM6. J. Biol. Chem. 282,
7656–7667
4 Ryazanova, L. V., Rondon, L. J., Zierler, S., Hu, Z., Galli,
J., Yamaguchi, T. P., Mazur, A., Fleig, A. and Ryazanov,
A. G. (2010) TRPM7 is essential for Mg2 + homeostasis in
mammals. Nat. Commun. 1, 109
5 Berggard, T., Miron, S., Onnerfjord, P., Thulin, E.,
Akerfeldt, K. S., Enghild, J. J., Akke, M. and Linse, S.
(2002) Calbindin D28k exhibits properties characteristic
of a Ca2 + sensor. J. Biol. Chem. 277, 16662–16672
6 Schweigel, M. and Martens, H. (2000) Magnesium
transport in the gastrointestinal tract. Front. Biosci. 5,
D666–D677
7 Flatman, P. W. (1991) Mechanisms of magnesium
transport. Annu. Rev. Physiol. 53, 259–271
8 Amasheh, S., Fromm, M. and Gunzel, D. Claudins of
intestine and nephron – a correlation of molecular tight
junction structure and barrier function. Acta Physiol. 201,
133–140
9 Fine, K. D., Santa Ana, C. A., Porter, J. L. and Fordtran,
J. S. (1991) Intestinal absorption of magnesium from food
and supplements. J. Clin. Invest. 88, 396–402
10 Quamme, G. A. (2008) Recent developments in intestinal
magnesium absorption. Curr. Opin. Gastroenterol. 24,
230–235
11 Fujita, H., Sugimoto, K., Inatomi, S., Maeda, T., Osanai,
M., Uchiyama, Y., Yamamoto, Y., Wada, T., Kojima, T.,
Yokozaki, H. et al. (2008) Tight junction proteins
claudin-2 and -12 are critical for vitamin D-dependent
Ca2 + absorption between enterocytes. Mol. Biol. Cell 19,
1912–1921
12 Wallach, S. (1990) Effects of magnesium on skeletal
metabolism. Magnes. Trace Elem. 9, 1–14
13 Rude, R. K., Kirchen, M. E., Gruber, H. E., Meyer, M. H.,
Luck, J. S. and Crawford, D. L. (1999) Magnesium
deficiency-induced osteoporosis in the rat: uncoupling of
bone formation and bone resorption. Magnes. Res. 12,
257–267
14 Quamme, G. A. (1993) Laboratory evaluation of
magnesium status. Renal function and free intracellular
magnesium concentration. Clin. Lab. Med. 13, 209–223
15 Le Grimellec, C., Roinel, N. and Morel, F. (1973)
Simultaneous Mg, Ca, P, K, Na and Cl analysis in rat
tubular fluid. II. During acute Mg plasma loading.
Pflugers Arch. 340, 197–210
16 Le Grimellec, C., Roinel, N. and Morel, F. (1973)
Simultaneous Mg, Ca, P, K, Na and Cl analysis in rat
tubular fluid. I. During perfusion of either inulin or
ferrocyanide. Pflugers Arch. 340, 181–196
17 Greger, R. (1985) Ion transport mechanisms in thick
ascending limb of Henle’s loop of mammalian nephron.
Physiol. Rev. 65, 760–797
18 Quamme, G. A. and Smith, C. M. (1984) Magnesium
transport in the proximal straight tubule of the rabbit.
Am. J. Physiol. 246, F544–F550
19 Le Grimellec, C. (1975) Micropuncture study along the
proximal convoluted tubule. Electrolyte reabsorption in
first convolutions. Pflugers Arch. 354, 133–150
20 de Rouffignac, C., Corman, B. and Roinel, N. (1983)
Stimulation by antidiuretic hormone of electrolyte
tubular reabsorption in rat kidney. Am. J. Physiol. 244,
F156–F164
21 Hou, J., Paul, D. L. and Goodenough, D. A. (2005)
Paracellin-1 and the modulation of ion selectivity of tight
junctions. J. Cell Sci. 118, 5109–5118
22 Desfleurs, E., Wittner, M., Simeone, S., Pajaud, S., Moine,
G., Rajerison, R. and Di Stefano, A. (1998)
Calcium-sensing receptor: regulation of electrolyte
transport in the thick ascending limb of Henle’s loop.
Kidney Blood Press. Res. 21, 401–412
Drug-induced alterations in Mg2 + homoeostasis 11
23 Brunette, M. G., Vigneault, N. and Carriere, S. (1974)
Micropuncture study of magnesium transport along the
nephron in the young rat. Am. J. Physiol. 227, 891–896
24 Thebault, S., Alexander, R. T., Tiel Groenestege, W. M.,
Hoenderop, J. G. and Bindels, R. J. (2009) EGF increases
TRPM6 activity and surface expression. J. Am. Soc.
Nephrol. 20, 78–85
25 Glaudemans, B., van der Wijst, J., Scola, R. H.,
Lorenzoni, P. J., Heister, A., van der Kemp, A. W.,
Knoers, N. V., Hoenderop, J. G. and Bindels, R. J. (2009)
A missense mutation in the Kv1.1 voltage-gated
potassium channel-encoding gene KCNA1 is linked to
human autosomal dominant hypomagnesemia. J. Clin.
Invest. 119, 936–942
26 Topf, J. M. and Murray, P. T. (2003) Hypomagnesemia
and hypermagnesemia. Rev. Endocr. Metab. Disord. 4,
195–206
27 Meij, I. C., Koenderink, J. B., van Bokhoven, H., Assink,
K. F., Groenestege, W. T., de Pont, J. J., Bindels, R. J.,
Monnens, L. A., van den Heuvel, L. P. and Knoers, N. V.
(2000) Dominant isolated renal magnesium loss is caused
by misrouting of the Na + ,K + -ATPase γ -subunit. Nat.
Genet. 26, 265–266
28 Meij, I. C., Saar, K., van den Heuvel, L. P., Nuernberg, G.,
Vollmer, M., Hildebrandt, F., Reis, A., Monnens, L. A.
and Knoers, N. V. (1999) Hereditary isolated renal
magnesium loss maps to chromosome 11q23. Am. J.
Hum. Genet. 64, 180–188
29 Geven, W. B., Monnens, L. A., Willems, H. L., Buijs,
W. C. and ter Haar, B. G. (1987) Renal magnesium
wasting in two families with autosomal dominant
inheritance. Kidney Int. 31, 1140–1144
30 Stuiver, M., Lainez, S., Will, C., Terryn, S., Gunzel, D.,
Debaix, H., Sommer, K., Kopplin, K., Thumfart, J.,
Kampik, N. B. et al. (2011) CNNM2, encoding a
basolateral protein required for renal Mg2 + handling, is
mutated in dominant hypomagnesemia. Am. J. Hum.
Genet. 88, 333–343
31 Meyer, T. E., Verwoert, G. C., Hwang, S. J., Glazer, N. L.,
Smith, A. V., van Rooij, F. J., Ehret, G. B., Boerwinkle, E.,
Felix, J. F., Leak, T. S. et al. (2011) Genome-wide
association studies of serum magnesium, potassium, and
sodium concentrations identify six loci influencing serum
magnesium levels. PLoS Genet. 6, e1001045
32 Groenestege, W. M., Thébault, S., van der Wijst, J., van
den Berg, D., Janssen, R., Tejpar, S., van den Heuvel, L. P.,
van Cutsem, E., Hoenderop, J. G., Knoers, N. V. and
Bindels, R. J. (2007) Impaired basolateral sorting of
pro-EGF causes isolated recessive renal hypomagnesemia.
J. Clin. Invest. 117, 2260–2267
33 Huang, C. L. and Kuo, E. (2007) Mechanism of
hypokalemia in magnesium deficiency. J. Am. Soc.
Nephrol. 18, 2649–2652
34 Yamamoto, M., Yamaguchi, T., Yamauchi, M., Yano, S.
and Sugimoto, T. (2011) Acute-onset hypomagnesemia-
induced hypocalcemia caused by the refractoriness of
bones and renal tubules to parathyroid hormone. J. Bone
Miner. Metab. 29, 752–755
35 Anast, C. S., Mohs, J. M., Kaplan, S. L. and Burns, T. W.
(1972) Evidence for parathyroid failure in magnesium
deficiency. Science 177, 606–608
36 Schlingmann, K. P., Sassen, M. C., Weber, S., Pechmann,
U., Kusch, K., Pelken, L., Lotan, D., Syrrou, M., Prebble,
J. J., Cole, D. E. et al. (2005) Novel TRPM6 mutations in
21 families with primary hypomagnesemia and secondary
hypocalcemia. J. Am. Soc. Nephrol. 16, 3061–3069
37 Arnaud, M. J. (2008) Update on the assessment of
magnesium status. Br. J. Nutr. 99 (Suppl. 3), S24–S36
38 Abrams, S. A. and Wen, J. P. (1999) Methodologies for
using stable isotopes to assess magnesium absorption and
secretion in children. J. Am. Coll. Nutr. 18, 30–35
39 Feillet-Coudray, C., Coudray, C., Tressol, J. C., Pepin,
D., Mazur, A., Abrams, S. A. and Rayssiguier, Y. (2002)
Exchangeable magnesium pool masses in healthy women:
effects of magnesium supplementation. Am. J. Clin. Nutr.
75, 72–78
40 Agus, Z. S. (1999) Hypomagnesemia. J. Am. Soc.
Nephrol. 10, 1616–1622

C The Authors Journal compilation 
C 2012 Biochemical Society
12 A. L. Lameris and others
41 Quamme, G. A. and de Rouffignac, C. (2000) Epithelial
magnesium transport and regulation by the kidney. Front.
Biosci. 5, D694–D711
42 Quamme, G. A. (1981) Effect of furosemide on calcium
and magnesium transport in the rat nephron. Am. J.
Physiol. 241, F340–F347
43 Monroy, A., Plata, C., Hebert, S. C. and Gamba, G.
(2000) Characterization of the thiazide-sensitive
Na + -Cl − cotransporter: a new model for ions and
diuretics interaction. Am. J. Physiol. Renal Physiol. 279,
F161–F169
44 Hollifield, J. W. (1986) Thiazide treatment of
hypertension. Effects of thiazide diuretics on serum
potassium, magnesium, and ventricular ectopy. Am. J.
Med. 80, 8–12
45 Grieff, M. and Bushinsky, D. A. (2011) Diuretics and
disorders of calcium homeostasis. Semin. Nephrol. 31,
535–541
46 Nijenhuis, T., Vallon, V., van der Kemp, A. W., Loffing, J.,
Hoenderop, J. G. and Bindels, R. J. (2005) Enhanced
passive Ca2 + reabsorption and reduced Mg2 + channel
abundance explains thiazide-induced hypocalciuria and
hypomagnesemia. J. Clin. Invest. 115, 1651–1658
47 Dai, L. J., Friedman, P. A. and Quamme, G. A. (1997)
Cellular mechanisms of chlorothiazide and cellular
potassium depletion on Mg2 + uptake in mouse distal
convoluted tubule cells. Kidney Int. 51, 1008–1017
48 Quamme, G. A. (1997) Renal magnesium handling: new
insights in understanding old problems. Kidney Int. 52,
1180–1195
49 Reilly, R. F. and Ellison, D. H. (2000) Mammalian distal
tubule: physiology, pathophysiology, and molecular
anatomy. Physiol. Rev. 80, 277–313
50 Gray, A., Dull, T. J. and Ullrich, A. (1983) Nucleotide
sequence of epidermal growth factor cDNA predicts a
128,000-molecular weight protein precursor. Nature 303,
722–725
51 Le Gall, S. M., Menton, P., Manduit, P. and Dreux, C.
(2004) The sequential cleavage of membrane anchored
pro-EGF requires a membrane serine protease other than
kallikrein in rat kidney. Regul. Pept. 122, 119–129
51a Breyer, J. A. and Coher, S. (1990) The epidermal growth
factor precursor isolated from murine kidney membranes.
Chemical characterization and biological properties.
J. Biol. Chem. 265, 16564–16570
52 Ikari, A., Sanada, A., Sawada, H., Okude, C., Tonegawa,
C. and Sugatani, J. (2011) Decrease in transient receptor
potential melastatin 6 mRNA stability caused by
rapamycin in renal tubular epithelial cells. Biochim.
Biophys. Acta 1806, 1502–1508
53 Fakih, M. G., Wilding, G. and Lombardo, J. (2006)
Cetuximab-induced hypomagnesemia in patients with
colorectal cancer. Clin. Colorectal Cancer 6, 152–156
54 Cao, Y., Liao, C., Tan, A., Liu, L. and Gao, F. (2010)
Meta-analysis of incidence and risk of hypomagnesemia
with cetuximab for advanced cancer. Chemotherapy 56,
459–465
55 Tejpar, S., Piessevaux, H., Claes, K., Piront, P.,
Hoenderop, J. G., Verslype, C. and van Cutsem, E. (2007)
Magnesium wasting associated with epidermal-
growth-factor receptor-targeting antibodies in colorectal
cancer: a prospective study. Lancet Oncol. 8,
387–394
56 Dimke, H., van der Wijst, J., Alexander, T. R., Meijer, I.
M., Mulder, G. M., van Goor, H., Tejpar, S., Hoenderop,
J. G. and Bindels, R. J. (2010) Effects of the EGFR
inhibitor erlotinib on magnesium handling. J. Am. Soc.
Nephrol. 21, 1309–1316
57 Epstein, M., McGrath, S. and Law, F. (2006)
Proton-pump inhibitors and hypomagnesemic
hypoparathyroidism. N. Engl. J. Med. 355, 1834–1836
58 Cundy, T. and Dissanayake, A. (2008) Severe
hypomagnesaemia in long-term users of proton-pump
inhibitors. Clin. Endocrinol. 69, 338–341
59 Regolisti, G., Cabassi, A., Parenti, E., Maggiore, U. and
Fiaccadori, E. (2010) Severe hypomagnesemia during
long-term treatment with a proton pump inhibitor. Am. J.
Kidney Dis. 56, 168–174

C The Authors Journal compilation 
C 2012 Biochemical Society
60 Kuipers, M. T., Thang, H. D. and Arntzenius, A. B.
(2009) Hypomagnesaemia due to use of proton pump
inhibitors: a review. Neth. J. Med. 67, 169–172
61 Hoorn, E., Van Der Hoek, J., De Man, R., Kuipers, E.,
Bolwerk, C. and Zietse, R. (2010) A case series of proton
pump inhibitor-induced hypomagnesemia. Am. J. Kidney
Dis. 56, 112–116
62 Furlanetto, T. W. and Faulhaber, G. A. (2011)
Hypomagnesemia and proton pump inhibitors: below the
tip of the iceberg. Arch. Intern. Med. 171, 1391–1392
63 Insogna, K. (2009) The effect of proton pump-inhibiting
drugs on mineral metabolism. Am. J. Gastroenterol. 104
(Suppl. 2), S2–S4
64 Wright, M., Sullivan, R., Gaffney-Stomberg, E., Caseria,
D., O’Brien, K., Proctor, D., Simpson, C., Kerstetter, J.
and Insogna, K. (2010) Inhibiting gastric acid production
does not affect intestinal calcium absorption in young,
healthy individuals: a randomized, crossover, controlled
clinical trial. J. Bone Miner. Res. 25, 2205–2211
65 Thongon, N. and Krishnamra, N. (2011) Omeprazole
decreases magnesium transport across Caco-2
monolayers. World J. Gastroenterol. 17, 1574–1583
66 Shah, G. M. and Kirschenbaum, M. A. (1991) Renal
magnesium wasting associated with therapeutic agents.
Miner. Electrolyte Metab. 17, 58–64
67 Wilkinson, R., Lucas, G. L., Heath, D. A., Franklin, I. M.
and Boughton, B. J. (1986) Hypomagnesaemic tetany
associated with prolonged treatment with
aminoglycosides. Br. Med. J. 292, 818–819
68 Sieber, M., Hoffmann, D., Adler, M., Vaidya, V. S.,
Clement, M., Bonventre, J. V., Zidek, N., Rached, E.,
Amberg, A., Callanan, J. J. et al. (2009) Comparative
analysis of novel noninvasive renal biomarkers and
metabonomic changes in a rat model of gentamicin
nephrotoxicity. Toxicol. Sci. 109, 336–349
69 Mingeot-Leclercq, M. P. and Tulkens, P. M. (1999)
Aminoglycosides: nephrotoxicity. Antimicrob. Agents
Chemother. 43, 1003–1012
70 Sassen, M. C., Kim, S. W., Kwon, T. H., Knepper, M. A.,
Miller, R. T., Frøkiaer, J. and Nielsen, S. (2006)
Dysregulation of renal sodium transporters in
gentamicin-treated rats. Kidney Int. 70, 1026–1037
71 Tzovaras, V., Tsimihodimos, V., Kostara, C., Mitrogianni,
Z. and Elisaf, M. (2011) Aminoglycoside-induced
nephrotoxicity studied by proton magnetic resonance
spectroscopy of urine. Nephrol. Dial. Transplant. 26,
3219–3224
72 Ward, D. T., Maldonado-Perez, D., Hollins, L. and
Riccardi, D. (2005) Aminoglycosides induce acute cell
signaling and chronic cell death in renal cells that express
the calcium-sensing receptor. J. Am. Soc. Nephrol. 16,
1236–1244
73 Ward, D. T., McLarnon, S. J. and Riccardi, D. (2002)
Aminoglycosides increase intracellular calcium levels and
ERK activity in proximal tubular OK cells expressing the
extracellular calcium-sensing receptor. J. Am. Soc.
Nephrol. 13, 1481–1489
74 Mani, S. (1992) Pentamidine-induced renal magnesium
wasting. AIDS 6, 594–595
75 Shah, G. M., Alvarado, P. and Kirschenbaum, M. A.
(1990) Symptomatic hypocalcemia and hypomagnesemia
with renal magnesium wasting associated with
pentamidine therapy in a patient with AIDS. Am. J. Med.
89, 380–382
76 Gradon, J. D., Fricchione, L. and Sepkowitz, D. (1991)
Severe hypomagnesemia associated with pentamidine
therapy. Rev. Infect. Dis. 13, 511–512
77 Wang, J. J., Freeman, A. I., Gaeta, J. F. and Sinks, L. F.
(1970) Unusual complications of pentamidine in the
treatment of Pneumocystis carinii pneumonia. J. Pediatr.
77, 311–314
78 Lachaal, M. and Venuto, R. C. (1989) Nephrotoxicity and
hyperkalemia in patients with acquired
immunodeficiency syndrome treated with pentamidine.
Am. J. Med. 87, 260–263
79 Andoh, T. F., Burdmann, E. A., Fransechini, N.,
Houghton, D. C. and Bennett, W. M. (1996) Comparison
of acute rapamycin nephrotoxicity with cyclosporine and
FK506. Kidney Int. 50, 1110–1117

80 da Silva, C. A., de Bragança, A. C., Shimizu, M. H.,
Sanches, T. R., Fortes, M. A., Giorgi, R. R., Andrade, L.
and Seguro, A. C. (2009) Rosiglitazone prevents
sirolimus-induced hypomagnesemia, hypokalemia, and
downregulation of NKCC2 protein expression. Am. J.
Physiol. Renal Physiol. 297, F916–F922
81 Laniado-Laborı́n, R. and Cabrales-Vargas, M. N. (2009)
Amphotericin B: side effects and toxicity. Rev. Iberoam
Micol. 26, 223–227
82 Barton, C. H., Pahl, M., Vaziri, N. D. and Cesario, T.
(1984) Renal magnesium wasting associated with
amphotericin B therapy. Am. J. Med. 77, 471–474
83 Crumpacker, C. S. (1992) Mechanism of action of
foscarnet against viral polymerases. Am. J. Med. 92, 3S–7S
84 Huycke, M. M., Naguib, M. T., Stroemmel, M. M., Blick,
K., Monti, K., Martin-Munley, S. and Kaufman, C. (2000)
A double-blind placebo-controlled crossover trial of
intravenous magnesium sulfate for foscarnet-induced
ionized hypocalcemia and hypomagnesemia in patients
with AIDS and cytomegalovirus infection. Antimicrob.
Agents Chemother. 44, 2143–2148
84a Stünzi, H. and Perrin, D. D. (1979) Stability constants of
metal complexes of phosphonoacetic acid. J. Inorg.
Chem. 10, 309–319
84b Noormohamed, F. H., Youte, M. S., Tang, B.,
Martin-Munley, S., Gazzard, B. G. and Lant, A. F. (1996)
Foscarnet-induced changes in plasma concentrations of
total and ionized calcium and magnesium in HIV-positive
patients. Antivir. Ther. 1, 172–179
85 Kim, H. C., Hwang, E. A., Han, S. Y., Park, S. B., Kim,
H. T. and Cho, W. H. (2004) Primary
immunosuppression with tacrolimus in kidney
transplantation: three-year follow-up in a single center.
Transplant. Proc. 36, 2082–2083
86 June, C. H., Thompson, C. B., Kennedy, M. S., Nims, J.
and Thomas, E. D. (1985) Profound hypomagnesemia
and renal magnesium wasting associated with the use of
cyclosporine for marrow transplantation. Transplantation
39, 620–624
87 Ahmadi, F., Naseri, R. and Lessan-Pezeshki, M. (2009)
Relation of magnesium level to cyclosporine and
metabolic complications in renal transplant recipients.
Saudi J. Kidney Dis. Transpl. 20, 766–769
88 Sabbagh, F., El Tawil, Z., Lecerf, F., Hulin, A., Maurois,
P., Dartevelle, P., Bac, P. and German-Fattal, M. (2008)
Impact of cyclosporine A on magnesium homeostasis:
clinical observation in lung transplant recipients and
experimental study in mice. Transplantation 86, 436–444
89 Chang, C. T., Hung, C. C., Tian, Y. C., Yang, C. W. and
Wu, M. S. (2007) Ciclosporin reduces paracellin-1
expression and magnesium transport in thick ascending
limb cells. Nephrol. Dial. Transplant. 22, 1033–1040
90 Ikari, A., Okude, C., Sawada, H., Takahashi, T., Sugatani,
J. and Miwa, M. (2008) Down-regulation of
TRPM6-mediated magnesium influx by cyclosporin A.
Naunyn. Schmiedebergs Arch. Pharmacol. 377, 333–343
91 Ledeganck, K. J., Boulet, G. A., Horvath, C. A., Vinckx,
M., Bogers, J. J., Van Den Bossche, R., Verpooten, G. A.
and De Winter, B. Y. (2011) Expression of renal distal
tubule transporters TRPM6 and NCC in a rat model of
cyclosporine nephrotoxicity and the effect of EGF
treatment. Am. J. Physiol. Renal Physiol. 301, F486–F493
92 Lote, C. J., Thewles, A., Wood, J. A. and Zafar, T. (2000)
The hypomagnesaemic action of FK506: urinary
excretion of magnesium and calcium and the role of
parathyroid hormone. Clin. Sci. 99, 285–292
93 Nijenhuis, T., Hoenderop, J. G. and Bindels, R. J. (2004)
Downregulation of Ca2 + and Mg2 + transport proteins
in the kidney explains tacrolimus (FK506)-induced
hypercalciuria and hypomagnesemia. J. Am. Soc.
Nephrol. 15, 549–557
94 Jeon, S. H., Kim, S. J., Kim, J. S. and Kang, H. S. (2009)
Immunosuppressant FK506 decreases the intracellular
magnesium in the human osteoblast cell by inhibiting the
ERK1/2 pathway. Life Sci. 84, 23–27
95 Lee, C. T., Ng, H. Y., Lien, Y. H., Lai, L. W., Wu, M. S.,
Lin, C. R. and Chen, H. C. (2011) Effects of cyclosporine,
tacrolimus and rapamycin on renal calcium transport and
vitamin D metabolism. Am. J. Nephrol. 34, 87–94
Drug-induced alterations in Mg2 + homoeostasis 13
96 Lajer, H. and Daugaard, G. (1999) Cisplatin and
hypomagnesemia. Cancer Treat. Rev. 25, 47–58
97 Bearcroft, C. P., Domizio, P., Mourad, F. H., Andre, E. A.
and Farthing, M. J. (1999) Cisplatin impairs fluid and
electrolyte absorption in rat small intestine: a role for
5-hydroxytryptamine. Gut 44, 174–179
98 Mavichak, V., Coppin, C. M., Wong, N. L., Dirks, J. H.,
Walker, V. and Sutton, R. A. (1988) Renal magnesium
wasting and hypocalciuria in chronic cis-platinum
nephropathy in man. Clin. Sci. 75, 203–207
99 Markmann, M., Rothman, R., Reichman, B., Hakes, T.,
Lewis, Jr, J. L., Rubin, S., Jones, W., Almadrones, L. and
Hoskins, W. (1991) Persistent hypomagnesemia following
cisplatin chemotherapy in patients with ovarian cancer. J.
Cancer Res. Clin. Oncol. 117, 89–90
100 Kroning, R., Lichtenstein, A. K. and Nagami, G. T. (2000)
Sulfur-containing amino acids decrease cisplatin
cytotoxicity and uptake in renal tubule epithelial cell
lines. Cancer Chemother. Pharmacol. 45, 43–49
101 Yokoo, K., Murakami, R., Matsuzaki, T., Yoshitome, K.,
Hamada, A. and Saito, H. (2009) Enhanced renal
accumulation of cisplatin via renal organic cation
transporter deteriorates acute kidney injury in
hypomagnesemic rats. Clin. Exp. Nephrol. 13, 578–584
102 Kutsal, E., Aydemir, C., Eldes, N., Demirel, F., Polat, R.,
Taspnar, O. and Kulah, E. (2007) Severe hypermagnesemia
as a result of excessive cathartic ingestion in a child
without renal failure. Pediatr. Emerg. Care 23, 570–572
103 Birrer, R. B., Shallash, A. J. and Totten, V. (2002)
Hypermagnesemia-induced fatality following epsom salt
gargles. J. Emerg. Med. 22, 185–188
104 Lu, J. F. and Nightingale, C. H. (2000) Magnesium sulfate
in eclampsia and pre-eclampsia: pharmacokinetic
principles. Clin. Pharmacokinet. 38, 305–314
105 Clark, B. A. and Brown, R. S. (1992) Unsuspected morbid
hypermagnesemia in elderly patients. Am. J. Nephrol. 12,
336–343
106 Nordt, S. P., Williams, S. R., Turchen, S., Manoguerra, A.,
Smith, D. and Clark, R. F. (1996) Hypermagnesemia
following an acute ingestion of Epsom salt in a patient
with normal renal function. J. Toxicol. Clin. Toxicol. 34,
735–739
107 Tofil, N. M., Benner, K. W. and Winkler, M. K. (2005)
Fatal hypermagnesemia caused by an Epsom salt enema: a
case illustration. South. Med. J. 98, 253–256
108 Gerard, S. K., Hernandez, C. and Khayam-Bashi, H.
(1988) Extreme hypermagnesemia caused by an overdose
of magnesium-containing cathartics. Ann. Emerg. Med.
17, 728–731
109 Weber, C. A. and Santiago, R. M. (1989)
Hypermagnesemia. A potential complication during
treatment of theophylline intoxication with oral activated
charcoal and magnesium-containing cathartics. Chest 95,
56–59
110 Smilkstein, M. J., Smolinske, S. C., Kulig, K. W. and
Rumack, B. H. (1988) Severe hypermagnesemia due to
multiple-dose cathartic therapy. West. J. Med. 148,
208–211
111 Smilkstein, M. J., Steedle, D., Kulig, K. W., Marx, J. A.
and Rumack, B. H. (1988) Magnesium levels after
magnesium-containing cathartics. J. Toxicol. Clin.
Toxicol. 26, 51–65
112 Herzog, P. and Holtermuller, K. H. (1982) Antacid
therapy: changes in mineral metabolism. Scand. J.
Gastroenterol. Suppl. 75, 56–62
113 Whang, R. (1978) Antacid-induced hypermagnesemia.
West. J. Med. 129, 256
114 Humphrey, M., Kennon, S. and Pramanik, A. K. (1981)
Hypermagnesemia from antacid administration in a
newborn infant. J. Pediatr. 98, 313–314
115 McLaughlin, S. A. and McKinney, P. E. (1998)
Antacid-induced hypermagnesemia in a patient with
normal renal function and bowel obstruction. Ann.
Pharmacother. 32, 312–315
116 Okahira, M., Kubota, M., Iguchi, K., Usui, S. and Hirano,
K. (2008) Regulation of aquaporin 3 expression by
magnesium ion. Eur. J. Pharmacol. 588, 26–32

C The Authors Journal compilation 
C 2012 Biochemical Society
 14 A. L. Lameris and others
117 Ikarashi, N., Mochiduki, T., Takasaki, A., Ushiki, T.,
Baba, K., Ishii, M., Kudo, T., Ito, K., Toda, T., Ochiai, W.
and Sugiyama, K. (2011) A mechanism by which the
osmotic laxative magnesium sulphate increases the
intestinal aquaporin 3 expression in HT-29 cells. Life Sci.
88, 194–200
118 Ikarashi, N., Ushiki, T., Mochizuki, T., Toda, T., Kudo,
T., Baba, K., Ishii, M., Ito, K., Ochiai, W. and Sugiyama,
K. (2011) Effects of magnesium sulphate administration
on aquaporin 3 in rat gastrointestinal tract. Biol. Pharm.
Bull. 34, 238–242
119 Zaman, F. and Abreo, K. (2003) Severe hypermagnesemia
as a result of laxative use in renal insufficiency. South.
Med. J. 96, 102–103
120 Qureshi, T. and Melonakos, T. K. (1996) Acute
hypermagnesemia after laxative use. Ann. Emerg. Med.
28, 552–555
121 Tatsuki, M., Miyazawa, R., Tomomasa, T., Ishige, T.,
Nakazawa, T. and Arakawa, H. (2011) Serum magnesium
concentration in children with functional constipation
treated with magnesium oxide. World J. Gastroenterol.
17, 779–783
Received 24 January 2012; accepted 31 January 2012
Published on the Internet 12 March 2012, doi:10.1042/CS20120045

C The Authors Journal compilation 
C 2012 Biochemical Society
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122 Gren, J. and Woolf, A. (1989) Hypermagnesemia
associated with catharsis in a salicylate-intoxicated
patient with anorexia nervosa. Ann. Emerg. Med. 18,
200–203
123 Ashton, M. R., Sutton, D. and Nielsen, M. (1990) Severe
magnesium toxicity after magnesium sulphate enema in a
chronically constipated child. Br. Med. J. 300, 541
124 Brown, A. T. and Campbell, W. A. (1978) Hazards of
hypertonic magnesium enema therapy. Arch. Dis. Child.
53, 920
125 Shah, G. M., Winer, R. L., Cutler, R. E., Arieff, A. I.,
Goodman, W. G., Lacher, J. W., Schoenfeld, P. Y.,
Coburn, J. W. and Horowitz, A. M. (1987) Effects of a
magnesium-free dialysate on magnesium metabolism
during continuous ambulatory peritoneal dialysis. Am. J.
Kidney Dis. 10, 268–275
126 Weisinger, J. R. and Bellorin-Font, E. (1998) Magnesium
and phosphorus. Lancet 352, 391–396
127 Kraft, M. D., Btaiche, I. F., Sacks, G. S. and Kudsk, K. A.
(2005) Treatment of electrolyte disorders in adult patients
in the intensive care unit. Am. J. Health. Syst. Pharm. 62,
1663–1682