Eur J Clin Pharmacol (1990) 39:29-31
EuropeanJ. . . . ,of ( ~ [ ~ ( ~ ( ~
Does N-Acetylcysteine increase the excretion of trace metals
(calcium, magnesium, iron, zinc and copper) when given orally?
E. Hjortsr 1, J. S. F o m s g a a r d 1, and N. F o g h - A n d e r s e n 2
DepartmentsofAnaesthesiologyand 2 ClinicalChemistry, HerlevHospital, University of Copenhagen, Denmark
Received: November 27, 1989/Accepted in revised form: February 9, 1990
Summary. N-Acetylcysteine (NAC) is known to decrease
the exacerbation rate in patients with chronic bronchitis.
It has also been shown that N A C has both an oxygen-radi-
cal scavenger and a heavy-metal chelating effect in high
intravenous doses. In a study lasting 5 weeks, 10 healthy
volunteers were treated with N A C 200 mg t. d.s. for two
weeks. The concentrations of trace metals (Ca, Mg, Fe, Zn
& Cu) in plasma were measured weekly and daily in a
morning spot urine during the investigation.
No significant change in plasma concentration or ex-
cretion was found during the two weeks of treatment, im-
plying that additional administration of trace metals is un-
necessary for patients treated perorally with a therapeutic
dose of NAC.
Key words: Acetylcysteine, metal excretion; trace metals,
NAC
The accumulation of viscid mucus is a problem in chronic
lung diseases, such as chronic bronchitis and cystic fi-
brosis. The high viscosity of the mucus may contribute to
atelectasis and infections. A therapy aimed at a direct in-
fluence on the mucus would be rational. The viscosity of
the mucus is related to the disulphide bonds in the muco-
protein [1]. Inhalation of N-acetylcysteine (NAC) can
mediate a sulphhydryldisulphide interchange reaction
and thereby reduce the viscosity of mucus [2, 3]. When
given orally, N A C may increase the plasma glutathione
concentration and thereby reduce the volume of mucus [4,
5]. Long-term peroral treatment with N A C decreases the
exacerbation rate in chronic bronchitis [6, 7], which may
be due to an effect on mucoregulation.
N A C also scavenges oxygen radicals, but its bioavaila-
bility after oral administration is probably too low for the
drug to have an important effect of this type [8, 9]. N A C
also acts as a chelator of heavy metals; Lorber et al. have
shown in vitro and in vivo that N A C has a heavy metal-
complexing potential [10]. In their clinical study N A C 3 g
was given intravenously over a 6 h period. In chrysother-
apy it has been possible to increase urine gold excretion
5>Besec@e|
@ Springer-Verlag 1990
with N A C [11]. Gofrey et al. either used intravenous N A C
2 to 9 g given over a period varying from 2 to 6 h, or a com-
bination of IV and oral NAC. The total doses varied from
20 to 130 mg- kg- 1. day- 1. Similarly, the urinary excretion
of zinc was increased by intravenous N A C 140 mg.
kg- 1. day-1 [12]. The chelating properties of N A C may be
related to its resemblance to cysteine, which has a high af-
finity in vitro for copper, iron and zinc. N A C might form
ultrafiltrable complexes with these trace metals in plasma
and so increase their glomerular filtration. Tubular reab-
sorption may also be blocked by certain non-reabsorbable
complexes of the trace metals. This mechanism is known
to occur after the infusion of citrate [13] and sulphate [14],
which lower the concentration of calcium in plasma and
increase its urinary output.
N A C has been shown to have both oxygen-radical
scavenging and heavy-metal chelating effects in high in-
travenous doses [9, 12]. It is not known if N A C also inter-
feres with the naturally existing trace metals; nor is it
known if the peroral doses used for the long-term treat-
ment of chronic lung diseases (200 mg t. d. s.) might have
some chelating potential. The purpose of the present
study was to seek any possible chelating effect of N A C
200 mg t. d. s. on the trace metals (Ca, Mg, Fe, Zn & Cu).
Material and methods
Foliowing acceptance by the "Regional Ethical Committee" and the
National Health Service, 10 healthy volunteers took part in the in-
vestigation, which lasted for 5 weeks. The volunteers had no known
renal dysfunction, and none was taking drugs regularly. The mean
age of the 7 women and 3 men involved was 41 y (range 24-50 y).
The first two weeks served as the control period. During the follow-
ing two weeks, the volunteers were treated with NAC 200 mg t. d. s.
(Mucomyst| followed by a drug free period of 1 week.
Once a week a blood sample was analysed for plasma calcium,
magnesium, iron, zinc, copper and creatinine. The concentrations of
Ca, Mg, Fe, Zn, Cu and creatinine were measured daily in a morning
spot urine.
The volunteers were on normal food intake, with no special limi-
tation on the intake of trace metals. Each volunteer functioned as
his/her own control.
30 E. Hjortsr et al.: N-Acetylcysteine and metal excretion
Table 1. Mean plasma concentrations of trace metals and creatinine AII samples from one person were measured in duplicate in the
in plasma from 10 healthy volunteers before, during and after low- same series. Calcium, iron and creatinine in plasma were measured
dose N-acetylcysteine. with a SMAC (Technicon, Terrytown, USA), and creatinine in urine
d 1, d 2 and d 3 are pre-treatment values from the first two weeks, d 4 was measured with a RA 1000 (Technicon). Copper, magnesium and
and d5 represent one and two weeks of treatment and the last zinc in plasma, and calcium, copper, iron, magnesium and zinc in
sample, d 6, was taken following one further week without treat- urine were measured with a Perkin-Elmer 403 atomic absorption
ment. spectrophotometer. The urine was evaporated to dryness and re-dis-
Each value is the mean of 10 duplicate determinations. solved in one tenth of its original volume of nitric acid (0.3 tool. 1- z)
before measuring copper and iron. The relative imprecision (CV)
Concentrations in plasma was less than 2% for all variables except copper (3%) and iron (4%)
dl d2 d3 d4 d5 d6 in urine.
Student's t-test for paired observations was used for statistical
Calcium mmol/1 2.34 2.32 2.32 2.32 2.34 2.34
(SD) (0.12) (0.08) (0.08) (0.08) (0.12) (0.10) analysis and values of P < 0.05 were considered statistically signifi-
cant.
Magnesium mmol/l 0 . 8 4 0.84 0.83 0.80 0.82 0.83
(SD) (0.05) (0.04) (0.04) (0.04) (0.05) (0.03)
Iron gmol/1 21.3 16.2 15.3 18.2 18.0 15.1 Results
(SD) (11.5) (5.4) (5.5) (5.6) (7.9) (4.9)
Zinc gmol/1 13.4 13.3 12.9 13.6 13.3 13.9 T h e plasma concentrations of the trace metals and crea-
(SD) (3.2) (2.0) (1.4) (2.4) (1.4) (1.5) tinine are shown in Table 1, and the urine levels in Table 2.
Copper gmol/1 15.9 15.7 15.2 15.1 15.9 15.8 T h e c o n c e n t r a t i o n of each trace metal in urine was
(SD) (1.9) (2.7) (1.8) (2.0) (2.1) (1.9) divided by its creatinine concentration (Table 3). The sub-
Creatinine Hmol/1 76 78 77 73 77 74 stance ratios are i n d e p e n d e n t of fluid v o l u m e and intake
(SD) (5) (8) (6) (5) (7) (7) and give a m o r e precise m e a s u r e of the excretion, N o stat-
istically significant change in the concentration or urinary
Table 2. Mean concentrations of trace metals and creatinine in urine excretion of calcium, magnesium, iron, zinc or c o p p e r was
from 10 healthy volunteers. Each person provided a morning urine o b s e r v e d during the two weeks on oral low dose N A C .
sample every day for five weeks. T h e 95% confidence limits indicated that any change not
wl and w2 are pre-treatment values, w3 and w4 represent samples considered to be due to a statistical Type 2 error would
during N-acetylcysteine treatment, and w 5 is the period after treat- have b e e n too small to be of any clinical importance.
ment. Each value is the mean of 70 duplicate measurements.
Concentrations in urine
wl w2 w3 w4 w5 Discussion
Calcium mmol/1 5.0 4.4 4.0 4.0 4.5
(SD) (4.0) (2.7) (2.5) (2.1) (3.0) N A C is often used in the t r e a t m e n t of patients with chron-
Magnesium mmol/1 4.9 4.3 4.2 4.2 4.5 ic bronchitis [4, 5], w h o m a y be given continuous treat-
(SD) (2.9) (2.1) (1.8) (2.2) (2.2) m e n t with doses of 600 mg. day -1. N o m a j o r side effects
Iron gmol/l 0.71 0.74 0.75 0.73 0.70 have b e e n described as a result of this dose. It has b e e n
(SD) (0.31) (0.33) (0.30) (0.28) (0.36) shown, however, that N A C can have a chelating effect
Zinc gmol/1 7.5 7.2 7.5 7.2 7.5 following intravenous administration of higher doses
(SD) (5.0) (5.5) (4.4) (3.7) (4.7) [10-12]. A s the terminal half-life of N A C is 6.25 h after
oral administration [15] and steady state is obtained after
Copper gmol/I 0.24 0.24 0.24 0.24 0.25
(SD) (0.06) (0.06) (0.05) (0.04) (0.06) a b o u t 30 h, the present results represent a steady-state
period of 12 days.
Creatinine retool/1 12.4 10.7 11.1 10.9 11.7
(SD) (5.8) (4.9) (4.9) (3.7) (4.8) D u r i n g N A C t r e a t m e n t no significant change in the
urine excretion or plasma concentrations of the trace me-
tals was observed as c o m p a r e d to the control period. In
Table 3. Mean concentration ratios of trace metals and creatinine in particular, there was no increase during the last w e e k of
urine before, during and after treatment with N-acetylcysteine (data dosing.
from Table 2).
T h e study has shown, therefore, that oral administra-
Concentration ratios in urine tion of N A C 600 mg. d a y - 1 did not result in a depletion of
wl w2 w3 w4 w5 trace metals. This might be related to the very low bio-
Calcium/creatinine 0.42 0.42 0.39 0.38 0.40 availability of oral N A C with its ensuing low plasma con-
(SD) (0.34) (0.22) (0.24) (0.20) (0.25) centration.
A d d i t i o n a l administration of trace metals during
Magnesium/creatinine 0.42 0.42 0.42 0.40 0.41
(SD) (0.24) (0.16) (0.19) (0.16) (0.16) t r e a t m e n t with N A C in doses sufficient for mucoregula-
tion in chronic lung diseases is not necessary.
Iron/creatinine 10- s 6.7 8.6 7.8 7.4 7.4
(SD) (3.7) (6.1) (4.1) (3.7) (5.6) T h e previously observed chelating effect of N A C
[8-10] must have b e e n due to higher plasma concentra-
Z i n c / c r e a t i n i n e 10 -4 6.1 6.4 6.7 6.5 6.3
(SD) (3.3) (2.9) (2.0) (2.0) (2.3) tions t h a n those p r o d u c e d by 600 mg. d a y - 1 p. o.
Copper/creatinine 10-s 2.2 2.6 2.4 2.4 2.5 Acknowledgements. We thank Draco Denmark, especially Dr
(SD) (0.7) (1.0) (0.9) (0.6) (1.2) T. B Ibsen, for making the investigation possible.
E. Hjortsr et al.: N Acetylcysteine and metal excretion
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E. Hj orts0, M. D.
Department of Anaesthesiology
Rigshospitalet
Blegdamsvej 9
DK-2100 Copenhagen, Denmark