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Antimicrobial Agents and Chemotherapy, December 2001, p. 3451-3455, Vol. 45, No. 12
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.12.3451-3455.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Effects of Lansoprazole and Amoxicillin on Uptake
of [14C]Clarithromycin into Gastric Tissue in
Rats
Hiromi
Endo,*
Hideo
Yoshida,
Naoko
Ohmi, and
Shohei
Higuchi
Department of Drug Metabolism, Research
Center, Taisho Pharmaceutical Co., Ltd., 403, Saitama-shi, Saitama
330-8530, Japan
Received 24 March 2000/Returned for modification 15 November
2000/Accepted 17 September 2001
 |
ABSTRACT |
Triple therapy consisting of clarithromycin (CLR), lansoprazole
(LPZ), and amoxicillin (AMZ) is effective as eradication therapy for patients with peptic ulcer disease and Helicobacter
pylori infection. We evaluated the effects of LPZ and AMZ on the
uptake of [14C]CLR into the gastric tissue of rats. After
administration of [14C]CLR alone or in combination with
LPZ and AMZ, the distributions of [14C]CLR in the main
organs and gastrointestinal tissues were compared. LPZ and AMZ had no
effect on the distribution of [14C]CLR in any tissue
except gastric tissue. The concentration of radioactivity in gastric
tissue was several times higher when [14C]CLR was
administered orally together with LPZ than when it was administered
alone. The gastric emptying of [14C]CLR became smaller in
the case of the coadministration of LPZ. AMZ had no apparent influence
on the disposition of [14C]CLR. After the intravenous
administration of [14C]CLR, no effects of drug
coadministration were evident. In vitro uptake of
[14C]CLR into gastric tissue was enhanced in the case of
a high-pH environment. The uptake was not influenced by the
concurrent presence of LPZ and AMZ. These results suggest that the
penetration of [14C]CLR possibly depends on elevated
gastric pH, as gastric acid secretion was inhibited by LPZ, and this
may be a primary factor in explaining why the concentration of
[14C]CLR at the target site, gastric tissue, was enhanced
by the coadministration of LPZ.
| |
INTRODUCTION |
The association between active
gastritis and Helicobacter pylori was first reported by
Warren (24) and Marshall (13), and H. pylori-associated gastritis may be the cause of gastric ulcer.
Recently, clinical trials involving the use of antibiotics yielded
evidence that antibiotics can eradicate H. pylori (5, 6, 8, 17).
The macrolide antibiotic clarithromycin (CLR) is, to date, one of the
most active antimicrobial agents against H. pylori in vitro
(4). It is relatively stable in the presence of gastric acid (15) and has a high affinity for tissue
(10). The penicillin antibiotic amoxicillin (AMZ) also has
strong in vitro activity against H. pylori (7)
and is more stable than macrolides in gastric acid. Treatment with CLR
or AMZ alone in vivo, however, is rarely effective. The eradication
rate was 15 to 54% when CLR was administered alone (18)
and 20 to 30% when AMZ was administered alone (7). The
activities of both CLR and AMZ against H. pylori are
affected by pH, as the activities are reduced under acidic conditions (1, 4) and the levels of distribution of
the drugs to the gastric mucus and mucosa inhabited by H. pylori are insufficient. When a single antibiotic, CLR or AMZ, was
combined with a proton pump inhibitor (lansoprazole [LPZ])
(19), the eradication rates were 57 to 77% (20,
23). H. pylori was eradicated from 84 to 95% of
patients concomitantly prescribed LPZ, CLR, and AMZ (2, 11,
20).
To better comprehend the synergism, the effects of LPZ and AMZ on the
distribution of 14C-labeled CLR in rats were investigated,
with particular focus on the ability of CLR to penetrate gastric tissue.
| |
MATERIALS AND METHODS |
Chemicals.
[6-O-methyl-14C]CLR was
obtained from Daiichi Pure Chemicals Co., Ltd. (Tokyo, Japan). The
specific activity was 2.44 MBq/mg and the radiochemical purity was 96%
or higher, as determined on the basis of high-pressure liquid
chromatography (HPLC) analysis. Unlabeled CLR was synthesized at the
Research Center, Taisho Pharmaceutical Co., Ltd. (Saitama, Japan). LPZ
was obtained from Takeda Chemical Industries, Ltd. (Osaka, Japan). AMZ
was purchased from Sigma Chemical Co. (St. Louis, Mo.). All other
commercially available reagents and solvents were of either analytical
or HPLC grade.
Animals.
Male Wistar rats (age, 7 weeks) were purchased from
Nihon SLC Co., Ltd. (Shizuoka, Japan). The rats were fed a commercial food (MF; Oriental Yeast Co., Ltd., Tokyo, Japan) and water
freely throughout the acclimatization period and the study period
except for the day before the labeled compounds were administered. The rats weighed 193 to 221 g and were used for the study when they were 8 weeks of age.
Preparation of dosage form and administration of drug.
Rats
were given 5 mg of [14C]CLR, 10 mg of LPZ, and 10 mg of
AMZ per kg of body weight. These drugs for oral administration were
suspended in 5% gum arabic adjusted to pH 7.0 with 1 N KOH. For
intravenous administration, [14C]CLR was given in a
solution of saline, with equimolar amounts of HCl used to dissolve the
drug. An intravenous dose of AMZ was dissolved in 2.33%
KH2PO4-1.44% NaHCO3 isotonic
buffer (pH 7.4). The rats were distributed randomly into six groups,
with each group comprising three rats, and were given the drugs as
indicated in Table 1.
Effects of LPZ and AMZ on distribution of
[14C]CLR.
At 15, 30, 60, and 240 min after oral
administration of [14C]CLR (groups 1 to 3) and at 15 and
60 min after intravenous administration of [14C]CLR
(groups 4 to 6), the rats were anesthetized with either and whole blood
was withdrawn from the inferior aorta and placed into heparinized
containers. Plasma was obtained by centrifugation of the blood at 1,600 × g rpm for 10 min at 4°C. After the collection of
blood, the liver, kidney, heart, lung, stomach, and intestine (from
duodenum to ileum) were immediately excised and the gastrointestinal contents were collected from each animal. The stomach was separated into the forestomach and the glandular stomach. The duodenum was separated from the intestine. The radioactivity in each biological sample was dissolved with 0.5 to 1 ml of Soluene-350 (Packard Instrument Co., Inc., Meriden, Conn.) and was decolored by
adding 0.4 to 0.5 ml of 30% hydrogen peroxide. Then, 10 ml of
Insta-gel plus scintillator (Packard Instrument Co., Inc.) was added to the sample after neutralization with 0.5 to 1 ml of 1 N HCl. The radioactivity was measured with a liquid scintillation counter (LS6000TA; Beckman Instruments Inc., Fullerton, Calif.).
Preparation of drug solution for in vitro studies.
[14C]CLR was dissolved in an isotonic buffer of pH 2.3 (12 N HCl, 6.1 ml; citric acid, 7.7 g, NaOH, 2.9 g; NaCl,
3.6 g [all per liter]), pH 4.0 (12 N HCl, 3.8 ml; citric
acid, 12.6 g; NaOH, 4.8 g; NaCl, 2.1 g [all per
liter]), pH 5.5 (NaCl, 5.0 g;
Na2HPO4 · 12H2O, 1.2 g;
KH2PO4, 8.6 g [all per liter]), or pH
7.4 (NaCl, 4.0 g; Na2HPO4 · 12H2O, 19.1 g; KH2PO4, 1.8 g
[all per liter]) at a final concentration of 100 µg/ml. When the
drug interaction was investigated, LPZ or LPZ and AMZ at final
concentrations of 200 µg/ml were each added to the solution of
[14C]CLR.
In vitro uptake of [14C]CLR into gastric
tissue.
Rats were fasted for 16 h and were then killed by
withdrawal of whole blood, following anesthetization with ether. The
stomach was washed with about 10 ml of saline, the cardia and pylorus were tied, and then the entire stomach was immediately excised. A
solution of 1 ml of [14C]CLR in an isotonic buffer of pH
2.3, 4.0, 5.5, or 7.4 was injected through a needle into the excised
stomach sac, followed by incubation at 37°C for 1 h in 5 ml of
isotonic buffer of pH 7.4. After incubation, the radioactivities of the
buffers in the sac, incubation medium, and gastric tissue (forestomach
and glandular stomach, respectively) were determined in the same
manner as described above for the in vivo study.
In order to clarify the effects of LPZ and AMZ on the penetration of
[
14C]CLR, rats which were given drugs as indicated in
Table
1 were
used. One hour after the final administration of LPZ,
their stomachs
were washed with saline and excised. Then, isotonic
buffer plus
[
14C]CLR and LPZ or isotonic buffer plus
[
14C]CLR, LPZ, and AMZ was injected into the sacs and the
experiments
were continued as described
above.
Statistics.
The results are expressed as the means and
standard deviations. The significance of differences was evaluated by
variance analysis with the SAS/STAT package. A significance level of
0.01 was used for all tests.
| |
RESULTS |
Concentrations of radioactivity in main organs.
The
concentrations of radioactivity in the main organs 60 min after
administration of [14C]CLR are presented in Table
2. When [14C]CLR was
administered orally, the highest concentration of radioactivity was
found in the liver, followed in descending order by the concentrations in the lung, kidney, and heart. On the other hand, after intravenous administration, the concentration in the lung was the highest, being
approximately twice as high as that in the liver. LPZ and AMZ were not
observed to have any effect on the concentration of
[14C]CLR in any tissue.
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TABLE 2.
Concentrations of radioactivity in tissues 60 min after
oral or intravenous administration of [14C]CLR to rats
(groups 1 to 6)
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|
Concentration of radioactivity in gastrointestinal tissues.
The concentrations of radioactivity in gastrointestinal tissues after
the administration of [14C]CLR are shown in Fig.
1 and 2.
For both the oral and intravenous routes of administration, the
concentrations of radioactivity in all gastrointestinal tissues were
much higher than those in plasma. After oral administration, the
concentrations in the forestomach and glandular stomach were altered
significantly (P < 0.01) by coadministration of LPZ
(Fig. 1). During the first 60 min, the concentrations in the
forestomach and the glandular stomach were two to six times higher when
[14C]CLR was given together with LPZ (groups 2 and 3)
than when it was given alone (group 1). LPZ had no apparent effect on
the concentration of radioactivity in the duodenum. There were no
significant differences in the concentrations of radioactivity in any
of the gastrointestinal tissues between the dual-treatment group (group
2) and the triple-treatment group (group 3). On the other hand, in the
case of intravenous administration, the radioactivity in the glandular
stomach was three to four times higher than that in the forestomach
(Fig. 2). The coadministration of drugs had no effect on the
concentrations of radioactivity in gastric tissues, which is different
from the case for oral administration.
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FIG. 1.
Concentrations of radioactivity in gastrointestinal
tissues after oral administration of [14C]CLR to rats
(groups 1 to 3). Each value represents the mean±standard deviation for
three animals. Significant differences (P < 0.01) in
the concentrations of radioactivity in the forestomachs and glandular
stomachs were observed in groups 2 and 3 compared with those in group
1.
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FIG. 2.
Concentrations of radioactivity in gastrointestinal
tissues after intravenous administration of [14C]CLR to
rats (groups 4 to 6). Each value represents the mean ± standard
deviation for three animals.
|
|
Recovery of radioactivity in gastrointestinal contents.
The
recoveries of radioactivity in the stomach contents and the intestinal
contents after administration of [14C]CLR are shown in
Fig. 3. After oral administration, there
was a pronounced tendency (P < 0.0487) for the
recovery of radioactivity in the stomach contents observed after
[14C]CLR was administered together with LPZ (Groups 2 and
3) to be higher than that observed after [14C]CLR was
administered alone (group 1). During the first 60 min after
administration, the levels of recovery of radioactivity in the
intestinal contents of groups 2 and 3 were lower than that for group 1. On the other hand, after the intravenous administration of
[14C]CLR, no effect of LPZ on the recovery of
radioactivity in the gastrointestinal contents was detected. The
recovery of radioactivity in stomach contents (about 0.6%) and
intestinal contents (10 to 20%) was lower after intravenous
administration than that after oral administration.
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FIG. 3.
Recovery of radioactivity in gastrointestinal contents
after oral (p.o.) or intravenous (i.v.) administration of
[14C]CLR to rats (groups 1 to 6). Each value represents
the mean ± standard deviation for three animals.
|
|
In vitro uptake of radioactivity into gastric tissue.
[14C]CLR dissolved in isotonic buffer at various pHs was
injected into stomach sacs, and then the stomach sacs were incubated at
37°C. The uptake of radioactivity into glandular stomach and forestomach tissues depended significantly (P < 0.01)
on the pH environment. The highest level of uptake was observed at pH
7.4; the recoveries were 14.86% in glandular stomach tissue and
2.93% in forestomach tissue. The uptake decreased in the
descending order of pH 5.5, 4.0, and 2.3 (Fig.
4a). The coadministration of LPZ and AMZ
on the uptake of [14C]CLR into the gastric tissue was not
observed to have any effect (Fig. 4b and c). In all cases, there was
little recovery of radioactivity in the incubation medium.
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FIG. 4.
In vitro uptake of radioactivity in rat gastric tissue
after injection of [14C]CLR (100 µg/ml) into rat
stomach sacs. Each value represents the mean ± standard deviation
of three experiments. A significant difference (P < 0.01) in the recovery of radioactivity in the glandular stomach
and the forestomach was observed among the pH environments. (a)
[14C]CLR (100 µg/ml) alone; (b) [14C]CLR
(100 µg/ml) plus LPZ (200 µg/ml) after administration of LPZ (10 mg/kg for 4 days, orally); (c) [14C]CLR (100 µg/ml)
plus LPZ (200 µg/ml) and AMZ (200 µg/ml) after administration of
LPZ (10 mg/kg for 4 days orally).
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| |
DISCUSSION |
H. pylori naturally infects humans; over its evolution
the organism has become well suited to the environment of the gastric mucosa and mucus (12). The present study shows the
synergistic effects of LPZ and AMZ on the uptake of
[14C]CLR into rat gastric tissue, with both gastric
mucosa and mucus being target sites.
After both the oral and the intravenous administration of
[14C]CLR, the concentrations of radioactivity in the
liver, lung, kidney, heart, and gastrointestinal tissues, which were
much higher than those in blood and plasma, were the result of the high
degree of affinity of [14C]CLR for tissue. When
[14C]CLR was administered intravenously, radioactivity
was detected in the stomach contents, suggesting that
[14C]CLR may be secreted from gastric tissue. This may
explain why [14C]CLR was distributed selectively into the
glandular stomach containing foveolae gastricae and fundic glands which
had secreting cells, whereas the concentration of radioactivity in the
forestomach, which had no secreting cells, was low after intravenous
administration. In the case of oral administration, the concentrations
of radioactivity in both the forestomach and the glandular stomach were
similar, but these levels were higher than those after intravenous
administration. Thus, we propose two routes of [14C]CLR
uptake into the gastric tissue after oral administration: one is
penetration from gastric lumen, and the other is secretion through the
blood circulation. The synergistic effect of LPZ on the uptake of
radioactivity into the gastric tissue would be due to the penetration
of [14C]CLR and would have no influence on the secretion
of [14C]CLR. CLR is metabolized to the active metabolite
14-hydroxy CLR in humans (21), but the metabolic
reaction occurs at a low level in rats (22).
Furthermore, CLR is more stable in a high-pH environment (treatment
with LPZ). Hence, in the present study, the radioactivity that
penetrated into the gastric tissue and that was secreted through the
blood circulation may mainly be unchanged CLR in rats.
The level of gastric emptying of the radioactivity into the intestinal
contents was lower when [14C]CLR was coadministered with
LPZ than when it was administered alone. Proton pump inhibitors such as
omeprazole (16) and LPZ (9) had no effect on
the gastric emptying of a liquid meal. Therefore, it was interesting
that the gastric emptying of [14C]CLR after oral
administration was influenced by the coadministration of LPZ. A part of
the [14C]CLR dosed was trapped in the gastric mucus, and
the trapping ratio might be increased by the coadministration of LPZ.
To better comprehend the mechanism of enhanced penetration of
[14C]CLR by the coadministration of LPZ, the effects of
both pH and the presence of additional drugs were demonstrated in in
vitro experiments with excised stomach sacs. The uptake of
radioactivity into gastric tissue depended on the pH. The level of
penetration of CLR was greater at neutral pH and less at
acidic pH. As CLR is a base with a pKa of 8.76 (15), the percentage of the nonionized form is larger at
basic pH and the solubility of CLR in lipid may be enhanced. In
contrast, no direct drug interaction would exist regarding the
penetration of [14C]CLR. It was reported that the pH of
the gastric surface after oral dosing to rats with LPZ (10 mg/kg) was
elevated to about 6 and was significantly higher than that for the
vehicle (pH 2 to 3) (14). In addition, when omeprazole was
administered to healthy subjects, the viscosity of the gastric mucus
decreased when the intragastric pH was increased (3).
Therefore, in vivo the increase in the level of [14C]CLR
penetration would be due to the effect of LPZ on the gastric pH.
CLR shows excellent in vitro activity against H. pylori, and
the MIC is lower at basic pH (1, 4). In the present
study, not only the biological activity of CLR against H. pylori but also the penetration of CLR were enhanced in a high-pH
environment (treatment with LPZ). The penetration would be the primary
factor that affects CLR uptake into gastric tissue soon after
administration. On the other hand, the concentration related to
secretion is lower than that related to penetration, but it may exceed
the MIC in the high-pH environment (treatment with LPZ) for a long
time. In humans, CLR is metabolized to its active metabolite,
14-hydroxy CLR. Therefore, the penetration of CLR and the secretion of
both CLR and 14-hydroxy CLR may play important roles in the eradication of H. pylori, with a time lag. These synergistic effects
would lead to a highly effective means of eradication of H. pylori in clinical therapy.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Drug Metabolism, Research Center, Taisho Pharmaceutical Co., Ltd., 403, Yoshino-cho 1-chome, Saitama-shi, Saitama 330-8530, Japan. Phone: 81 48 663 1111. Fax: 81 48 652 7254. E-mail:
hiromi.endou{at}po.rd.taisho.co.jp.
| |
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Antimicrobial Agents and Chemotherapy, December 2001, p. 3451-3455, Vol. 45, No. 12
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.12.3451-3455.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Endo, H., Yoshida, H., Ohmi, N., Ohta, K., Higuchi, S., Suga, T.
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Abstract
Introduction
