Biomedicine & Pharmacotherapy 99 (2018) 18–24

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Original article

Antacids’ side effect hyperuricaemia could be alleviated by long-term T

aerobic exercise via accelerating ATP turnover rate
⁎
Shu Yuana, , Zhong-Wei Zhanga, Zi-Lin Lib
a
College of Resources, Sichuan Agricultural University, Chengdu, China
b
Department of Internal Medicine, Xijing Hospital, Medical University of the Air Force, Xi’an, China

A R T I C L E I N F O A B S T R A C T

Keywords: Hyperuricemia is the term for an abnormally high serum uric acid level. Many factors contribute to hyperur-
Antacids icemia, however no definite correlation between proton pump inhibitors (PPIs) and hyperuricemia has been
ATP metabolism reported before. Physical exercise also decreases serum uric acid levels. However, the detailed biochemical-
Hyperuricemia regulatory mechanisms remain unknown. Here we found that adenylate deaminase activities are much higher in
Physical exercise
hyperuricemia patients than in the healthy people. Therefore, the patients have higher levels of adenosine
Uric acid
metabolites hypoxanthine and uric acid. Acid-inhibitory drugs (antacids) significantly increased serum uric acid
level and may lead to gout in the hyperuricemia patient. Long-term aerobic exercise significantly increased
serum phosphorus and decreased serum ATP and its metabolites, and therefore decreased serum uric acid.
Antacids slow down the ATP turnover rate and result in serum uric acid elevation subsequently. While the long-
term aerobic exercise decreases serum uric acid levels by accelerating ATP turnover rate. The results imply that
long-term aerobic exercise may be a useful strategy to prevent and treat hyperuricaemia.

1. Introduction
Gout is a condition characterized by the deposition of monosodium
urate crystals in the joints or soft tissue. The four phases of gout include
asymptomatic hyperuricemia, acute gouty arthritis, intercritical gout
and chronic tophaceous gout. The peak incidence occurs in patients
30–50 years old, and the condition is much more common in men than
in women. Although gouty arthritis characteristically occurs in patients
with hyperuricemia, it is incorrect to equate hyperuricemia with clin-
ical gout [1]. Asymptomatic hyperuricemia is the term for an abnor-
mally high serum urate level, without gouty arthritis or nephrolithiasis.
Hyperuricemia is defined as a serum urate concentration greater than
7 mg per dL (416 μmol per L by the uricase method), the approximate
level at which urate is supersaturated in plasma [1]. Many factors
contribute to hyperuricemia, including genetics, insulin resistance,
hypertension, renal insufficiency, obesity, diet, use of diuretics and
some drugs (like salicylates), and consumption of alcoholic beverages
[2]. However, no definite correlation between acid-inhibitory drugs
(antacids) and hyperuricemia has been reported before [3]. Antacids,
like Ranitidine, are very commonly used in treatment of peptic ulcer
disease and gastroesophageal reflux disease. If they may cause hyper-
uricemia, such side effect is worth of highly attentions. Here we first
report antacids’ side effect – Hyperuricemia, which may lead to gout in
the patient with a basic high uric acid level. Antacids famotidine and
omeprazole also have this side effect. This hyperuricaemia is not related
with the sex steroids, but the decreased serum phosphorus level (by
retarding ATP turnover presumably).
There is an interesting example about the putative role of physical
exercise on hyperuricemia alleviation. In October 2015, one patient had
a 12-day travel (mostly mountain-climbing). Three days after the travel
(15 days without any antacid), his serum uric acid level decreased from
540 μmol/L to 500 μmol/L. So we assume that the sport may help re-
ducing serum uric acid. Physical exercise influences serum uric acid
levels that moderate exercise may counteract the cardiovascular pa-
thological mechanisms (by decreasing plasma renin activity and am-
bulatory heart rates) involved in the hyperuricemia and the associated
hypertension [4,5]. However, the detailed metabolic regulation me-
chanisms remain unknown. Here we investigated the relationships
among antacids, exercise, uric acid and ATP metabolism in ten hy-
perlipidemia patients and three healthy volunteers. Through the ana-
lysis to ATP metabolites, we presume that long-term aerobic exercise
decreases serum uric acid levels by accelerating ATP turnover rate
(indicated by the increase in serum phosphorus and decrease in serum
adenosine).

⁎
Corresponding author.
E-mail address: roundtree318@hotmail.com (S. Yuan).

https://doi.org/10.1016/j.biopha.2018.01.052
Received 22 November 2017; Received in revised form 20 December 2017; Accepted 5 January 2018
0753-3322/ © 2018 Elsevier Masson SAS. All rights reserved.
S. Yuan et al. Biomedicine & Pharmacotherapy 99 (2018) 18–24

HYPO, hypoxanthine; ADA, adenylatedeaminase. The experiment was repeated twice. The data are shown as the mean ± standard deviation. Different lowercase letters within a row indicate significant differences at 0.05 (P < 0.05) levels.
2. Patients and methods

336 ± 11d
430 ± 13b

1.1 ± 0.1b
1.4 ± 0.1b

9.3 ± 0.8b
7.5 ± 0.9c
9.3 ± 1.0c
9.2 ± 1.0c
12 ± 1.4b
15 ± 1.4a
Volunt3

female

never
2.1. Patients and healthy volunteers

No
63
Ten patients of moderate hyperlipidemia (with or without the gout

1.3 ± 0.1b
1.5 ± 0.1b

7.2 ± 0.7b
301 ± 11e
384 ± 12c

6.4 ± 0.8c
8.9 ± 0.9c
8.3 ± 0.8c
15 ± 1.5a
17 ± 1.5a
flare history) were enrolled with agreements. Their ages range from 34
Volunt2

never

to 65 and their basic uric acid level range from 492 to 611 μmol/L
male

No
45

(Table 1). For more conclusive, three healthy volunteers were also
enrolled with agreements (Table 1). All participants showed normal
0.92 ± 0.09c

hydration statuses. All participants provided their written informed

5.2 ± 0.6d
1.3 ± 0.1b
285 ± 10e
367 ± 11c

8.3 ± 1.0c

8.1 ± 1.0c

3.9 ± 0.4c
11 ± 1.3b

10 ± 1.1c
Volunt1

consent to participate in this study. The consent procedure was ap-

never
male

proved by the Ethics Committee of the Shanxi Public Health Clinical

No
31

Center in accordance with the Helsinki Declaration, revised 2008. And

the experiments were also approved by the Ethics Committee.
1.4 ± 0.1b
1.7 ± 0.1b
611 ± 21a
694 ± 24a

17 ± 1.6b
14 ± 1.3b
13 ± 1.4b
15 ± 1.5a
18 ± 1.7a
16 ± 1.4a
Patient10

attacked

attacked
male

2.2. Drug dosage and exercise frequency

39

Most people in the patient group have mild to moderate acid reflux
563 ± 19b

1.0 ± 0.1b
1.4 ± 0.1b
687 ± 21a

11 ± 1.2b
13 ± 1.4b
11 ± 1.3b
13 ± 1.4b
16 ± 1.6a
17 ± 1.6a

diseases. Therefore, the antacids were prescripted. Drug dosage and

Patient9

never

frequency: Oral administration of ranitidine (one capsule of 150 mg),

male

No
48

famotidine (one tablet of 20 mg) or omeprazole (one tablet of 20 mg) at

the bedtime (12 h before blood test) or in the morning (2 h before blood
644 ± 20a

1.7 ± 0.1a
2.1 ± 0.1a
518 ± 18c

13 ± 1.4b
14 ± 1.4b
19 ± 1.8a
21 ± 1.9a
18 ± 1.8a
21 ± 1.9a

test). To rule out the effects of dietary choice, the patients were asked to
attacked
Patient8

female

keep low-purine diet (such as avoidance of red meat, seafood, organ

No
58

meat and tea drinking) and alcohol prohibition during the ranitidine
administration (or the control test without ranitidine administration).
1.1 ± 0.1b
1.5 ± 0.1b
640 ± 20a
506 ± 18c

17 ± 1.6b
15 ± 1.7a
17 ± 1.7a
15 ± 1.4a

18 ± 1.7a
18 ± 1.7a

To study the relationship among ranitidine, uric acid and sex ster-
Patient7

oids (Fig. 1A), patient 1, patient 2 and patient 3 were engaged. Rani-
never
male

No
53

tidine (one capsule of 150 mg) was given every day for totally 5 days,
then every day for totally 10 days, then every 3 days for totally 15 days
566 ± 18b

1.2 ± 0.1b
1.5 ± 0.1b
682 ± 20a

17 ± 1.5b
17 ± 1.6a
19 ± 1.8a
14 ± 1.4a

17 ± 1.6a
16 ± 1.6a

and then every 3 days for totally 30 days. Then the ranitidine admin-
attacked

attacked
Patient6

female

istration was stopped for 15–30 days.

65

One-time exercise means 1600 m jogging with a speed of 35–60 s per

100 m (total duration of 16–28 min). Intensity and frequency of the
547 ± 17b

1.4 ± 0.1b
1.6 ± 0.1b
639 ± 19a

13 ± 1.4b

17 ± 1.6b
14 ± 1.3b
15 ± 1.6a
15 ± 1.4a

15 ± 1.4a

long-term physical exercise: 45 days, every day (one hour after supper),
attacked
Patient5

female

1600 m jogging with a speed of 35–60 s per 100 m (total duration of

No

12–21 h). Within a month before the physical exercise, the participants
52

were prohibited to any antacid administration. To rule out the effects of

0.91 ± 0.09c

dietary choice, the patients and the volunteers were asked to keep low-
545 ± 16b
667 ± 20a

1.1 ± 0.1c
12 ± 1.4b

11 ± 1.3b
14 ± 1.5b
15 ± 1.6a

18 ± 1.7a
16 ± 1.6a

purine diet and alcohol prohibition during the long-term exercise.

attacked

attacked
Patient4

male
62

2.3. Serum biochemical determination

1.1 ± 0.1b
1.4 ± 0.1b
618 ± 16a
492 ± 14c

17 ± 1.6b
16 ± 1.6a
19 ± 1.8a
15 ± 1.4a

18 ± 1.7a
18 ± 1.7a

Serum uric acid, lipid, estradiol, testosterone, phosphorus, calcium

Patient3
ATP metabolism and gout flare attacks after one-time ranitidine administration.

were measured in the fifth hospital of Chengdu (Chengdu, Sichuan,

never
male

No
42

China) at 9:00–10:00 a.m.. Uric acid was detected by the direct phos-
photungstic acid method [6]. Serum lipids were detected by the enzy-
1.2 ± 0.1b
1.5 ± 0.1b
647 ± 19a
510 ± 15c

16 ± 1.6b
15 ± 1.4a
17 ± 1.8a
13 ± 1.4a

16 ± 1.6a
17 ± 1.6a

matic assays (triglyceride was measured by the glycerol oxidase

attacked
Patient2

method) [7]. Estradiol and testosterone were detected by the magnetic

male

No

particles-based chemiluminescence immunoassay [8]. Serum phos-

45

phorus and calcium were detected by the atomic absorption spectro-

540 ± 17b
658 ± 19a

1.8 ± 0.1a
2.2 ± 0.1a

photometry method [9].

18 ± 1.6a
20 ± 1.8a
17 ± 1.6a
20 ± 1.8a
20 ± 1.8a
19 ± 1.8a
Patient1

For the pharmacokinetic studies of ranitidine, famotidine and

never
male

omeprazole on uric acid, serum phosphorus and calcium (Fig. 1B), the
No
34

patient 1 was engaged. Serum uric acid, phosphorus and calcium levels
Volunteer or Hyperuricaemia patient

were detected at 0–48 h after the one-time administration. This ex-

Serum adenosine after ranitidine ad.

Serum HYPO after ranitidine admin.

ADA activity after ranitidine admin.

Serum ATP after ranitidine admin.
Gout flare after ranitidine admin.

periment was repeated twice.

Serum adenosine level (mmol/L)
Uric acid after ranitidine admin.
Uric acid basic level (μmol/L)

Blood serum ATP, adenosine and hypoxanthine levels were determined

Serum HYPO level (mmol/L)
Serum ATP level (mmol/L)

by the high-pressure liquid chromatography (HPLC) [10]. Aliquots of 20 μl

Basic ADA activity (U/L)

were applied to a reversed-phase HPLC (Agilent Technologies, Santa Clara,

CA, USA) using a C18 column. The elution was carried out by applying a
Gout flare history

linear gradient from the solvent A (5 mM tetrabutyl-ammonium chloride,

60 mM KH2PO4, pH 6.0) to the solvent B (30% methanol to the solvent A)
over a 40 min period (flow rate of 1.5 mL/min). Standard samples of ade-
Gender
Table 1

Age

nosine, hypoxanthine (HYPO) and uric acid were obtained from Sigma
Chemical Comp. (Sigma-Aldrich, St Louis, MO, USA).

19
S. Yuan et al.
Fig. 1. Relationship among antacids, uric acid, serum phosphorus and serum calcium. (A) Relationship among ranitidine, uric acid and sex steroids. Data were collected from the patient
1, patient 2 and patient 3 respectively (marked with different color depths). (B) Kinetic effects of ranitidine, famotidine and omeprazole on uric acid, serum phosphorus and calcium. Data
were collected from the patient 1. The experiment was repeated twice. Error bar indicates the standard deviation.
Serum adenosine deaminase activity was measured by a dry che-
mical technique (Vitro 75° Johnson & Johnson, USA), using reflectance
for final determination [11,12].
2.4. Statistical analysis
Most experiments were repeated twice for both the hyperuricaemia
patient group and the healthy volunteer group (n = 3), unless stated
otherwise. Significant differences among the hyperlipidemia patients
and the healthy volunteers were analyzed according to Ducan’s multi-
plication range test at the 5% level. The correlations between the serum
uric acid and other biochemical components were analyzed by calcu-
lating the Pearson product-moment correlation coefficient (r value).
ANOVA (Analysis of Variance) was performed by using the software
SPSS v22.0.
3. Results
3.1. Hyperuricemia induced by antacids
A 34-year-old male patient (Patient 1) was diagnosed with hyper-
uricaemia and acid reflux disease. His basic serum uric acid con-
centration was 540 μmol/L (Table 1). 5-day and 10-day continuous
administration of ranitidine (every day) resulted in a high uric acid
level of 663 μmol/L and 672 μmol/L respectively. Then 15-day and 30-
day interrupted administration of ranitidine (every 3 days) resulted in a
uric acid level of 616 and 582 μmol/L respectively. Then following 15-
day and 30-day rest without ranitidine administration reduced uric acid
level to 548 μmol/L and 511 μmol/L respectively (Fig. 1A). Similar
correlations between uric acid levels and ranitidine administrations
were acquired form the Patient 2 (a 45-year-old male patient with basic
20
Biomedicine & Pharmacotherapy 99 (2018) 18–24
serum uric acid level of 510 μmol/L) and the Patient 3 (a 42-year-old
male patient with basic serum uric acid level of 492 μmol/L) (Fig. 1A).
Everyday ranitidine administration got the highest serum uric acid
level, the ranitidine administration every 3 resulted in declined serum
uric acid level, and then serum uric acid level decreased gradually after
the stop of ranitidine administration (Fig. 1A). ANOVA (Analysis of
Variance) shows the impacts of ranitidine on serum uric acid were
significant in a dose-dependent manner (P < 0.05).
Besides ranitidine, famotidine and omeprazole are other commonly
used antacids [13]. Pharmacokinetic studies with antacids showed that
the uric acid levels were not significantly changed at 2 h, reached the
peak at 12 h, and decreased to the control level after 48 h (Fig. 1B).
This is not the unique case. On the Ehealthme website (http://www.
ehealthme.com/cd/uric+acid/ranitidine), by the time of 2016-
October-21, 23 side-effect cases were reported about the correlation
between ranitidine and elevated uric acid level (15 cases of moderate or
high correlations), including 8 long-term (more than 1 year) ranitidine
taking cases (6 cases of moderate or high correlations).
On www.ehealthme.com website, only 23 cases of hyperuricemia
were reported for the drug ranitidine (2% of the total side-effect re-
ports). Then why was the proportion of hyperuricemia in all the side-
effects such low? The patient 1 took Benzbromarone [14] once to treat
hyperuricemia that the uric acid was lowered to 286 μmol/L. After that,
one-time ranitidine administration increased the uric acid level to
372 μmol/L. Data from healthy volunteers, patients with or without
gout showed that increment of the uric acid level does not exceed 30%
(of the baseline value) or 120 μmol/L (Table 1). The values are still
within the normal range for most healthy people. This may be the
reason that the side effect of hyperuricemia has been merely reported
before.
S. Yuan et al. Biomedicine & Pharmacotherapy 99 (2018) 18–24

HYPO, hypoxanthine; ADA, adenylatedeaminase. One-time exercise means 1600 m jogging with a speed of 35–60 s per 100 m. The experiment was repeated twice. The data are shown as the mean ± standard deviation. Different lowercase letters
3.2. Relationship between antacids and sex steroids

336 ± 11d

1.1 ± 0.1b

9.2 ± 0.8b
331 ± 11c

1.0 ± 0.1c

7.5 ± 0.9c
7.2 ± 0.9c
9.2 ± 1.0c
12 ± 1.4b
12 ± 1.4b
Volunt3
To explore the possible mechanism of ranitidine-induced hyperur-
icaemia, estradiol and testosterone were detected accompanying with
the uric acid level (Fig. 1a). For patient 1, patient 2 and patient 3, serum

1.3 ± 0.1b
301 ± 11e
323 ± 11c

1.1 ± 0.1c

6.4 ± 0.8c
6.5 ± 0.8c
8.3 ± 0.8c
6.5 ± 0.7c
14 ± 1.5b
15 ± 1.5a
estradiol ranged from 11.8 to 16.2 pg/mL; while testosterone ranged

Volunt2
from 3.1 to 5.4 ng/mL. Neither of them was related with the ranitidine
administration (p > 0.05).

0.87 ± 0.09d
0.92 ± 0.09c
301 ± 10d

5.2 ± 0.6d
285 ± 10e

8.3 ± 1.0c
7.9 ± 1.0c
8.1 ± 1.0c
7.4 ± 1.0c

5.8 ± 0.6c
3.3. Relationship between antacids and serum phosphorus

Volunt1
Here we bring out another hypothetical mechanism: ranitidine-in-
duced uric acid elevation may be correlated with ATP turnover. ATP

1.4 ± 0.1b
1.3 ± 0.1b
611 ± 21a
599 ± 20a

14 ± 1.5b

14 ± 1.3b
15 ± 1.5a

16 ± 1.4a
15 ± 1.4a

13 ± 1.2a
turnover rate was usually monitored by the serum phosphorus level. For

Patient10
patient 1, 12 h after ranitidine administration, serum phosphorus de-
creased from 1.05 mmol/L to 0.87 mmol/L (the normal levels are
1.00–1.60 mmol/L), and serum calcium increased from 2.48 mmol/L to

0.92 ± 0.09c
2.55 mmol/L (the normal levels are 2.17–2.54 mmol/L) (Fig. 1B).

563 ± 19b

1.0 ± 0.1b
570 ± 18a

11 ± 1.2b
12 ± 1.3b
11 ± 1.3b
12 ± 1.2b
16 ± 1.6a
15 ± 1.5a
Serum phosphorus and calcium usually vary oppositely with a rela-

Patient9
tively stable product [15]. This kinetic study was repeated twice, and
ANOVA shows the impact of ranitidine on serum phosphorus (at 12 h)
was very significant (p = 0.010). Serum phosphorus and uric acid were

503 ± 17b
1.7 ± 0.1a
1.5 ± 0.1a
518 ± 18c

13 ± 1.4b
19 ± 1.8a
18 ± 1.7a
18 ± 1.8a
17 ± 1.6a

15 ± 1.4a
strong negatively correlated (r = − 0.997).

Patient8
In order to testify the effects of ranitidine on serum uric acid and
phosphorus in healthy people and gout patients, three healthy volun-
teers were enrolled (Table 1). After taking ranitidine for 12 h, uric acid

515 ± 16b
1.1 ± 0.1b
506 ± 18c

1.0 ± 0.1c

13 ± 1.4b
15 ± 1.7a
16 ± 1.6a
15 ± 1.4a

18 ± 1.7a
17 ± 1.8a
increased significantly, and phosphorus decreased significantly
Patient7
(P < 0.05). Three gout flares were reported here in the ten patients
with hyperuricaemia after one-time ranitidine administration (Table 1). 566 ± 18b
575 ± 18b
1.2 ± 0.1b
1.1 ± 0.1c

13 ± 1.4b
17 ± 1.6a
16 ± 1.6a
14 ± 1.4a

17 ± 1.6a
14 ± 1.6a
3.4. Relationship between ATP metabolism and uric acid production
Patient6

Adenylate deaminase (ADA) activities are much higher in all the

hyperuricemia patients than in the healthy volunteers (P < 0.05).
547 ± 17b
523 ± 17b
1.4 ± 0.1b
1.3 ± 0.1b
13 ± 1.4b
14 ± 1.4b

14 ± 1.4b
14 ± 1.3b
15 ± 1.4a

15 ± 1.5a
Therefore, the patients have higher levels of adenosine metabolites,
Patient5

such as hypoxanthine and uric acid (Table 1).

One-time ranitidine administration significantly increased serum
levels of ATP, adenosine and hypoxanthine in both the hyperuricemia
0.87 ± 0.09d
0.91 ± 0.09c

patients and the healthy volunteers (P < 0.05), although the adenylate
545 ± 16b
529 ± 16b

12 ± 1.4b
13 ± 1.4b
11 ± 1.3b
12 ± 1.3b
18 ± 1.7a
17 ± 1.6a
Patient4

deaminase itself was barely affected by the ranitidine administration

(P > 0.05; Table 1).

3.5. Relationship among physical exercise, ATP metabolism, triglyceride

504 ± 14b
1.1 ± 0.1b
492 ± 14c

1.0 ± 0.1c

14 ± 1.4b
16 ± 1.6a
16 ± 1.6a
15 ± 1.4a

18 ± 1.7a
18 ± 1.7a
Patient3

and uric acid production

Previous studies suggested that exercise elevated serum phosphorus

517 ± 15b
1.2 ± 0.1b

largely [16], but 1–2 times exercise (1600 m jogging with a speed of
510 ± 15c

1.1 ± 0.1c

14 ± 1.4b

13 ± 1.4b
15 ± 1.4a

13 ± 1.4a

16 ± 1.6a
17 ± 1.6a

within a row indicate significant differences at 0.05 (P < 0.05) levels.

Patient2

35–60 s per 100 m) cannot reduce the uric acid level significantly
(Table 2). So we designed a long-term exercise project for some patients
before the age of 60. After 45 days of jogging (everyday), uric acid
540 ± 17b
538 ± 17b

decreased, serum phosphorus increased, and calcium and triglyceride

1.8 ± 0.1a
1.6 ± 0.1a
18 ± 1.6a
18 ± 1.6a
17 ± 1.6a
15 ± 1.6a
20 ± 1.8a
17 ± 1.9a
Patient1

decreased respectively (Table 3). Compared with the data before ex-
ercise, all values were significantly different (P < 0.05). Long-term
ATP metabolism after one-time aerobic exercise.

aerobic exercise also helps alleviating gastroesophageal reflux for the

Serum adenosine after one-time exercise

patient 1. No serious reflux happened to him after the 15th day.

Serum basic adenosine level (mmol/L)
Volunteer or Hyper- uricaemia patient

One-time exercise decreased serum levels of ATP, adenosine and

Serum HYPO after one-time exercise

ADA activity after one-time exercise

Serum ATP after one-time exercise

Serum basic HYPO level (mmol/L)

hypoxanthine in both the hyperuricemia patients and the healthy vo-

Serum basic ATP level (mmol/L)
Uric acid after one-time exercise
Uric acid basic level (μmol/L)

lunteers (although insignificantly for some cases; Table 2). Never-

theless, the long-term exercise significantly decreased serum ATP and
Basic ADA activity (U/L)

its metabolites (Table 3).

4. Discussion

Here the side effect of antacids - serum uric acid elevation is firstly
Table 2

reported. Although the magnitude of the increasing does not exceed

30% or 120 μmol/L, it may be dangerous to the gout patients with high

21
S. Yuan et al. Biomedicine & Pharmacotherapy 99 (2018) 18–24

HYPO, hypoxanthine; ADA, adenylatedeaminase. Long-term exercise means 45 days of 1600 m jogging (everyday) with a speed of 35–60 s per 100 m. The experiment was repeated twice. The data are shown as the mean ± standard deviation.
basal uric acid levels. 30% gout flares were reported here after one-time

0.93 ± 0.10b

2.42 ± 0.18b
1.29 ± 0.09a
1.39 ± 0.11a

2.29 ± 0.18c
336 ± 11d
298 ± 10b
1.1 ± 0.1b

1.5 ± 0.1b

8.8 ± 0.9b
7.5 ± 0.9c
6.6 ± 0.7c
1.9 ± 0.2c

9.2 ± 1.0c
12 ± 1.4b
10 ± 1.1b
Volunt3 ranitidine administration (Table 1). Therefore, the study has an im-
portant clinical implication that the gout patients need cautions when
taking proton pump inhibitors (antacids). The reduction in the number
of gout flare attacks after the ranitidine administration may be because
that the increasing in uric acid does not always cause a gout flare, since

1.31 ± 0.10a
1.39 ± 0.10a
2.35 ± 0.18c
2.23 ± 0.17c
the ranitidine only induces a transient uric acid elevation.
287 ± 10b
1.3 ± 0.1b
1.1 ± 0.1b

7.9 ± 0.8b
e

6.4 ± 0.8c
6.2 ± 0.7c
1.6 ± 0.2c
1.3 ± 0.1c

8.3 ± 0.8c
15 ± 1.5a
13 ± 1.2a
301 ± 11

In females, estrogens fluctuate periodically, which could control the

Volunt2

uric acid level effectively [17]. However, testosterone may have a ne-
gative effect to uric acid excretion [18,19]. Both previous studies
[20,21] and our results (Fig. 1A) confirmed that ranitidine or famoti-
1.34 ± 0.11a
1.42 ± 0.12a
0.92 ± 0.09c
0.81 ± 0.08c

2.32 ± 0.18c
2.21 ± 0.17c
dine hardly affect testosterone level in male people. Thus changes of sex
1.3 ± 0.1d

5.2 ± 0.6d
261 ± 10b
e

8.3 ± 1.0c
7.9 ± 1.0c
8.1 ± 1.0c
7.1 ± 0.8c

1.1 ± 0.1c

5.7 ± 0.7c
285 ± 10

hormones are not the reason for ranitidine-induced uric acid elevation.
Volunt1

Adenylate deaminase (ADA; AMP aminohydrolase EC 3.5.4.6) cat-

alyzes the conversion of AMP to inosine monophosphate (IMP) and
ammonia [22]. Xanthine oxidase (XOD) then catalyzes hypoxanthine
oxidation to form xanthine, which could be further is oxidized to uric
1.15 ± 0.09b

2.41 ± 0.19b
2.30 ± 0.17b
1.39 ± 0.11a
1.4 ± 0.1b
1.1 ± 0.1b
a

504 ± 19a

3.1 ± 0.3a
2.1 ± 0.2a

14 ± 1.3b
15 ± 1.5a
12 ± 1.2a
16 ± 1.4a
13 ± 1.4a

15 ± 1.5a
611 ± 21

acid in livers [23–25]. ADA activities are much higher in all the hy-
Patient10

peruricemia patients than in the healthy volunteers. Therefore, the

patients have higher levels of adenosine metabolites, such as hypox-
anthine and uric acid (Table 1). Correlation between abnormal ADA
activity and primary gout has been reported before [26].
0.89 ± 0.09b

1.25 ± 0.10a
1.46 ± 0.12a
2.36 ± 0.17c
2.24 ± 0.17c

H2 histamine inhibitors or other antacids inhibit activity of the

b

1.0 ± 0.1b

9.7 ± 1.0b

9.1 ± 1.0b
2.2 ± 0.2b
485 ± 15a

1.9 ± 0.2a
11 ± 1.2b

11 ± 1.3b

16 ± 1.6a
15 ± 1.6a
563 ± 19

gastric H+/K+ ATPase, which should slow down the ATP turnover
Patient9

(utilization and regeneration) rate at the same time. Then the excessive
ATP may be metabolized into the adenine, which could be converted to
uric acid finally. When doing physical exercises (especially the long-
1.13 ± 0.09b
1.30 ± 0.11b
2.47 ± 0.18b
2.36 ± 0.18b

term aerobic physical training), ATP turnover is accelerated [27–29],

1.5 ± 0.2b
461 ± 16a
1.7 ± 0.1a
1.4 ± 0.1a
c

1.8 ± 0.2c

13 ± 1.4b
19 ± 1.8a
15 ± 1.4a
18 ± 1.8a
14 ± 1.4a

14 ± 1.5a
518 ± 18

which thereby reduces uric acid production ideally. A recent study to

Patient8

blood purines in young male adults showed that serum levels of ATP
and ADP were decreased after the aerobic exercise, in contrast with the
pre-exercise values, also indicating the accelerated ATP turnover [30].
Uric acid is the end product of purine metabolism and is produced
0.99 ± 0.09b

1.11 ± 0.09b
1.29 ± 0.12b
2.45 ± 0.18b
2.34 ± 0.18b
1.1 ± 0.1b
457 ± 15a

2.8 ± 0.2a
2.3 ± 0.2a
c

15 ± 1.7a
13 ± 1.2a
15 ± 1.4a
12 ± 1.1a

18 ± 1.7a
17 ± 1.6a
506 ± 18

normally by the body during tissue remodeling and breakdown. About

Patient7

only 20% of uric acid is derived from purines ingested in food [31].
Thus the gastric ATP metabolic efficiency may greatly impact uric acid
production (Fig. 2).
There are also some opposite reports that the excessive exercise may
0.96 ± 0.09b

1.18 ± 0.09b

2.43 ± 0.18b
2.33 ± 0.18b
1.37 ± 0.11a

cause purine nucleotide degradation and serum uric acid elevation

b

1.1 ± 0.1b

2.1 ± 0.2b
1.5 ± 0.2b
450 ± 13a

16 ± 1.6b
14 ± 1.2a
15 ± 1.4a
11 ± 1.0a

18 ± 1.7a
15 ± 1.6a
492 ± 14
Patient3

Different lowercase letters within a row indicate significant differences at 0.05 (P < 0.05) levels.

[32]. Plasma hypoxanthine has been shown to be elevated only after

the status exceeds the anaerobic threshold. Moderate exercise, which
keeps the status continuously below the anaerobic threshold, causes
neither blood lactic acid nor plasma hypoxanthine elevation. Appro-
1.28 ± 0.09a
1.44 ± 0.12a
2.38 ± 0.19c
2.25 ± 0.17c

priate aerobic exercise to a degree that does not exceed the threshold
b

1.2 ± 0.1b
1.0 ± 0.1b
475 ± 14a

1.7 ± 0.2c
1.3 ± 0.1c
15 ± 1.4b
13 ± 1.2a
13 ± 1.4a
11 ± 1.0a

16 ± 1.6a
17 ± 1.6a
510 ± 15

thus is expected to be beneficial for patients with gout/hyperuricemia

Patient2

[32].
Researches to quantify the beneficial effects of physical exercises are
relatively short. Aerobic exercise improves brain, cognition and cardi-
ovascular fitness in aging [33]. Recently, James D Watson published a
1.23 ± 0.10b
2.59 ± 0.18a
2.47 ± 0.18a
1.05 ± 0.07c
b

496 ± 15a
1.8 ± 0.1a
1.4 ± 0.1a

2.9 ± 0.2a
1.9 ± 0.2a

hypothesis on “Lancet” and suggested that physical exercise may be

18 ± 1.6a
15 ± 1.4a
17 ± 1.6a
13 ± 1.2a

20 ± 1.9a
16 ± 1.8a
540 ± 17
Patient1

needed to maintain a certain level of reactive oxygen species required

for normal disulphide bond formation in renascent peptides, which may
be closely related with onset and progression of type 2 diabetes and
ATP metabolism after long-term aerobic exercise.

Alzheimer’s disease [34]. Definitely therapeutic effects of physical ex-

Serum phosphorus after long-term exercise
Serum adenosine after long-term exercise

ercises on type 2 diabetes mellitus have been reported, such as the

Serum basic phosphorus level (mmol/L)

Serum calcium after long-term exercise

Serum basic adenosine level (mmol/L)
Volunteer or Hyper -uricaemia patient

Serum HYPO after long-term exercise

ADA activity after long-term exercise

improvements of glycemic control, body composition and cardiovas-

Triglyceride after long-term exercise

Serum basic calcium level (mmol/L)

Serum ATP after long-term exercise

Serum basic HYPO level (mmol/L)

cular fitness [35–37]. Data in this report suggest that exercise may help
Uric acid after long-term exercise

Basic triglyceride level (mmol/L)

Serum basic ATP level (mmol/L)
Uric acid basic level (μmol/L)

controlling uric acid and serum lipids and alleviating gastroesophageal

reflux. A large number of reports also confirm that exercise may help to
Basic ADA activity (U/L)

control hypoglycemia and hyperlipidemia [38].

Patient 1, patient 2 and patient 3, all of them had the moderate
hyperlipidemia. Their ages range from 34 to 45. The beneficial effects
of exercise on comprehensive hyperlipidemia, or in older people need
further studies. And the patient 1’s reflux esophagitis also was not very
Table 3

serious. The diagnosis showed that his illness was not a kind of
Zollinger-Ellison syndrome (ZES) [39]. Exercises may speed up

22
S. Yuan et al.
gastrointestinal peristalsis and alleviate reflux. But the effectiveness to
serious ZES patients requires further studies. Moreover, physical ex-
ercise should not apply to the patients with acute gout flares [40].
5. Conclusion
Here we found that antacids induce transient uric acid elevations.
Antacids slow down the ATP turnover rate (indicated by the decrease in
serum phosphorus and increase in serum ATP, adenosine and hypox-
anthine) and result in serum uric acid elevation subsequently. On the
contrary, the long-term aerobic exercise decreases serum uric acid le-
vels by accelerating ATP turnover rate (indicated by the increase in
serum phosphorus and decrease in serum ATP, adenosine and hypox-
anthine). This study of the relationship among antacids, exercise, uric
acid and serum phosphorus brings us a new idea of prevention and
treatments of hyperuricaemia. However the sample size is relatively
small and more systematically clinical investigations are required. To
further explore the mechanisms of antacids and physical exercises on
purine metabolism, more ATP metabolic enzymes should be tested in
the future studies.
Conflict of interest
The authors have declared that no conflict of interest exists.
Ethics statement
All participants (ten patients and three volunteers) provided their
written informed consent to participate in this study. The consent
procedure was approved by the Ethics Committee of the Shanxi Public
Health Clinical Center in accordance with the Helsinki Declaration,
revised 2008. And the experiments were also approved by the Ethics
Committee.
Acknowledgements
This work was funded by the Preeminent Youth Fund of Sichuan
Province (2015JQO045). We thank LetPub (www.letpub.com) for its
linguistic assistance during the preparation of this manuscript. And we
thank the three volunteers for the confirmation of the side effects of
ranitidine and the study of the effects of physical exercise.
23
Biomedicine & Pharmacotherapy 99 (2018) 18–24
Fig. 2. Diagram of relationship among antacids, physical exercise, ATP
metabolism and uric acid production.
References
[1] W.H. Mikkelson, H.J. Dodge, H. Valkenberg, The distribution of plasma uric acid
values in a population unselected as to gout and hyperuricemia, Am. J. Med. 39
(1965) 242–251.
[2] S.Z. Sun, B.D. Flickinger, P.S. Williamson-Hughes, M.W. Empie, Lack of association
between dietary fructose and hyperuricemia risk in adults, Nutr. Metab. 7
(2010) 16.
[3] M. Tran, J. Tafreshi, R.G. Pai, Review article: combination of clopidogrel and
proton pump inhibitors: implications for clinicians, J. Cardiovasc. Pharmacol. Ther.
15 (2010) 326–337.
[4] L. Liu, S. Lou, K. Xu, Z. Meng, Q. Zhang, K. Song, Relationship between lifestyle
choices and hyperuricemia in Chinese men and women, Clin. Rheumatol. 32 (2013)
233–239.
[5] F. Saladini, L. Mos, C. Fania, G. Garavelli, E. Casiglia, P. Palatini, Regular physical
activity prevents development of hypertension in young people with hyperuricemia,
J. Hypertens. 35 (2017) 994–1001.
[6] M.L. Matheke, G. Kessler, K.M. Chan, Interference of the chemotherapeutic agent
etoposide with the direct phosphotungstic acid method for uric acid, Clin. Chem. 33
(1987) 2109–2110.
[7] R.A. McPherson, K.D. Brown, R.P. Agarwal, G.A. Threatte, R.J. Jacobson,
Hydroxyurea interferes negatively with triglyceride measurement by a glycerol
oxidase method, Clin. Chem. 31 (1985) 1355–1357.
[8] T.B. Xin, S.X. Liang, X. Wang, H. Li, J.M. Lin, Determination of estradiol in human
serum using magnetic particles-based chemiluminescence immunoassay, Anal.
Chim. Acta 627 (2008) 277–284.
[9] B.J. Hunt, The estimation of magnesium in plasma, muscle and bone, by atomic
absorption spectrophotometry, Clin. Chem. 15 (1969) 979–996.
[10] W. Voelter, K. Zech, P. Arnold, G. Ludwig, Determination of selected pyrimidines,
purines and their metabolites in serum and urine by reversed-phase ion-pair
chromatography, J. Chromatogr. 199 (1980) 345–354.
[11] G. Ellis, D.M. Goldberg, A reduced nicotinamide adenine dinucleotide-linked ki-
netic assay for adenosine deaminase activity, J. Lab. Clin. Med. 76 (1970) 507–517.
[12] M.G. Brunstein, E.M. Jr Silveira, L.S. Chaves, et al., Increased serum adenosine
deaminase activity in schizophrenic receiving antipsychotic treatmen, Neurosci.
Lett. 414 (2007) 61–64.
[13] A. Gigante, I. Tagarro, Non-steroidal anti-inflammatory drugs and gastroprotection
with proton pump inhibitors: a focus on ketoprofen/omeprazole, Clin. Drug
Investig. 32 (2012) 221–233.
[14] R.C. Heel, R.N. Brogden, T.M. Speight, G.S. Avery, Benzbromarone: a review of its
pharmacological properties and therapeutic use in gout and hyperuricaemia, Drugs
14 (1977) 349–366.
[15] M.S. Calvo, The effects of high phosphorus intake on calcium homeostasis, Adv.
Nutr. Res. 9 (1994) 183–207.
[16] C. Karakukcu, Y. Polat, Y.A. Torun, A.K. Pac, The effects of acute and regular ex-
ercise on calcium, phosphorus and trace elements in young amateur boxers, Clin.
Lab. 59 (2013) 557–562.
[17] D. Adamopoulos, C. Vlassopoulos, B. Seitanides, P. Contoyiannis, P. Vassilopoulos,
The relationship of sex steroids to uric acid levels in plasma and urine, Acta
Endocrinol. 85 (1977) 198–208.
[18] M. Hosoyamada, Y. Takiue, T. Shibasaki, H. Saito, The effect of testosterone upon
the urate reabsorptive transport system in mouse kidney, Nucleosides Nucleotides
Nucleic Acids 29 (2010) 574–579.
[19] H. Kurahashi, M. Watanabe, M. Sugimoto, et al., Testosterone replacement elevates
S. Yuan et al.
the serum uric acid levels in patients with female to male gender identity disorder,
Endocr. J. 60 (2013) 1321–1327.
[20] C. Wang, K.L. Wong, K.C. Lam, C.L. Lai, Ranitidine does not affect gonadal function
in man, Br. J. Clin. Pharmacol. 16 (1983) 430–432.
[21] V. Savarino, M. Giusti, P. Scalabrini, et al., Famotidine has no significant effect on
gonadal function in man, Gastroenterol. Clin. Biol. 12 (1988) 19–22.
[22] G. van der Berghe, H.G. Hers, Abnormal AMP deaminase in primary gout, Lancet 2
(1980) 1090.
[23] Q. Hu, M. Zhou, H. Zhu, et al., (E)-2-(4-bromophenyl)-1-(2, 4-dihydroxyphenyl)
ethanone oxime is a potential therapeutic agent for treatment of hyperuricemia
through its dual inhibitory effects on XOD and URAT1, Biomed. Pharmacother. 86
(2017) 88–94.
[24] F. Liu, C. Deng, W. Cao, G. Zeng, X. Deng, Y. Zhou, Phytochemicals of Pogostemon
cablin (Blanco) Benth. aqueous extract: their xanthine oxidase inhibitory activities,
Biomed. Pharmacother. 89 (2017) 544–548.
[25] W. Huijuan, C. Xiaoxu, S. Rui, L. Xinghui, T. Beibei, M. Jianchun, Qi-Zhu-Xie-Zhuo-
Fang reduces serum uric acid levels and ameliorates renal fibrosis in hyperuricemic
nephropathy rats, Biomed. Pharmacother. 91 (2017) 358–365.
[26] N.L. Edwards, I.H. Fox, Disorders associated with purine and pyrimidine metabo-
lism, Spec. Top. Endocrinol. Metab. 6 (1984) 95–140.
[27] G. Layec, J.D. Trinity, C.R. Hart, et al., In vivo evidence of an age-related increase in
ATP cost of contraction in the plantar flexor muscles, Clin. Sci. 126 (2014)
581–592.
[28] A.M. Rivera-Brown, W.R. Frontera, Principles of exercise physiology: responses to
acute exercise and long-term adaptations to training, PM&R 4 (2012) 797–804.
[29] M. Casas, S. Buvinic, E. Jaimovich, ATP signaling in skeletal muscle: from fiber
plasticity to regulation of metabolism, Exerc. Sport Sci. Rev. 42 (2014) 110–116.
[30] C.E. Moritz, B.C. Teixeira, L. Rockenbach, A. Reischak-Oliveira, E.A. Casali,
24
Biomedicine & Pharmacotherapy 99 (2018) 18–24
A.M. Battastini, Altered extracellular ATP, ADP, and AMP hydrolysis in blood serum
of sedentary individuals after an acute, aerobic, moderate exercise session, Mol.
Cell. Biochem. 426 (2017) 55–63.
[31] N. Schlesinger, Dietary factors and hyperuricaemia, Curr. Pharm. Des. 11 (2005)
4133–4138.
[32] H. Yamanaka, Y. Kawagoe, A. Taniguchi, et al., Accelerated purine nucleotide de-
gradation by anaerobic but not by aerobic ergometer muscle exercise, Metabolism
41 (1992) 364–369.
[33] S.B. Chapman, S. Aslan, J.S. Spence, et al., Shorter term aerobic exercise improves
brain, cognition, and cardiovascular fitness in aging, Front. Aging Neurosci. 5
(2013) 75.
[34] J.D. Watson, Type 2 diabetes as a redox disease, Lancet 383 (2014) 841–843.
[35] S. Balducci, M. Sacchetti, J. Haxhi, et al., Physical exercise as therapy for type 2
diabetes mellitus, Diabetes Metab. Res. Rev. 30 (S1) (2014) 13–23.
[36] C. Lackinger, S. Haider, L. Kosi, J. Harreiter, Y. Winhofer, A. Kautzky-Willer,
Potential of a sports club-based exercise program for improving physical activity in
type 2 diabetes mellitus, J. Phys. Act. Health 12 (2015) 1221–1228.
[37] F. Najafipour, M. Mobasseri, A. Yavari, et al., Effect of regular exercise training on
changes in HbA1c, BMI and VO2max among patients with type 2 diabetes mellitus:
an 8-year trial, BMJ Open Diabetes Res. Care 5 (2017) e000414.
[38] M.S. Hedrington, S.N. Davis, Sexual dimorphism in glucose and lipid metabolism
during fasting, hypoglycemia, and exercise, Front. Endocrinol. 6 (2015) 61.
[39] R.M. Zollinger, E.H. Ellison, Primary peptic ulcerations of the jejunum associated
with islet cell tumors of the pancreas, Ann. Surg. 142 (1955) 709–723.
[40] S. O’Donnell, C. Rusu, S. Bernatsky, et al., Exercise/physical activity and weight
management efforts in canadians with self-reported arthritis, Arthri.Care Res. 65
(2013) 2015–2023.