Extract
Note: Please read the complete
full text with Figures and Tables at
Introduction
For a drug taken orally in solid dosage preparations,
dissolution, a prerequisite to movement across the intestinal
wall, is the first step during its gastrointestinal absorption.
Factors controlling dissolution include surface exposed to
the solvent, solubility of the compound, pH of the medium,
stirring rate around the dissolving particle, gastric empty,
and intestinal motility[1]. For bases or acids with low
aqueous solubility, 2 methods of increasing the dissolution have
been considered: use of salt and use of an acidic or a basic
environment. Of these, using a salt generally results in faster
dissolution. Considering this, many drugs are administered
as salts, and domperidone is an example. Domperidone is a
potent peripheral dopaminergic antagonist, which has been
reported as being effective in functional gastrointestinal
disorders, such as dyspepsia, gastroesophageal reflux,
nausea, and vomiting. It is usually co-administered with
antacids, alginates, and antisecretory compounds, primarily
H2 receptor antagonists and proton pump inhibitors in the
treatment of gastro-esophageal reflux disease
(GERD)[2]. Domperidone has been marketed worldwide since 1978. It is
available in 2 formulations: free-base tablets and maleate salt
tablets. In vitro dissolution tests have shown that maleate
salt dissolves more rapidly than the free base in neutral
environment. In vivo studies have shown that in healthy,
fasting patients, the free base and maleate salt have
demonstrated a good bioequivalence in the extent and the rate of
absorption[3], but the absorption of the free base is
significantly decreased by the prior administration of 300 mg
cimetidine combined with sodium bicarbonate solution (100
mL of 0.5 mol/L). This indicates that reduced gastric acidity
impairs the absorption of the base[3,4]. Therefore,
domperi-done base is not recommended be taken with antacids and
antisecretory agents, at least not simultaneously.
To optimize the therapeutic benefit in GORD
patients, proton pump inhibitors are more usually co-administered with
domperidone. Jiang et al have reported that antireflux therapy
(including 20 mg oral omeprazole once daily and 10 mg
domperidone 3 times a day for 6 weeks) may improve
pulmonary function and inhibit bronchial hyper-responsiveness
in asthmatic patients with GORD[5]. However, their effects
on the absorption of domperidone, both as free base and
maleate salt, are unclear. In the present study, we compared
the influence of omeprazole on the pharmacokinetics of both
domperidone base and domperidone maleate salt.
Materials and methods
Patients Ten healthy, male, Chinese patients ranging in
age from 20 to 27 years (median age, 22 years), in weight from
60 to 76 kg (67.1 kg±5.6 kg), and in height from 165 to 180 cm
(175 cm±6 cm) were enrolled in this study. Before enrolment,
each patient was considered to be in good health through
medical history, physical examination, electrocardiograms,
and routine laboratory tests. No medication was used for at
least 2 weeks before the study, and alcohol was forbidden
within 72 h prior to drug administration.
Ethics The study was approved by the Independent
Ethics Committee of the People's Hospital of Liaoning
Province (Shenyang, China) and was in full compliance with the
principles of the `Declaration of Helsinki' (current revision)
and the `Good Clinical Practice' guidelines. Written informed
consent was obtained from each patient before the study.
Study design This investigation was conducted in an
open, randomized, 2-period crossover study with a washout
period of 7 d. In each study period, the patients were
administered a single oral dose of 10 mg domperidone as free-base
tablet (Motilium, Janssen, Xi'an, China) or maleate salt
tablet (Domperidone maleate tablet, Hanmi, Tianjin, China)
on d 1, and 20 mg of omeprazole (Losec, AstraZeneca, Wuxi,
China) twice daily on d 2 and 3 and once on d 4. A single
dose of 10 mg domperidone as a free-base tablet or maleate
salt tablet was given at 4 h after administration of omeprazole
on d 4. On the study days, the drugs were administered in
the fasting state, and the patients continued to fast for 2 h
after drug administration. Standard meals were provided at
2, 5, and 10 h post-dose.
Sample collection In each study period, blood samples
(4 mL) were collected from the forearm vein and placed in
heparinized tubes prepared prior to domperidone
administration and at 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24, and 30 h
after domperidone administration on d 1 and 4, respectively.
The samples were then centrifuged at
1500×g for 10 min. Separated plasma was stored frozen (-20°C) until the assay.
Domperidone assay Plasma concentrations of
domperi-done were determined using a validated liquid
chromatography_tandem mass spectrometry
method[6]. Protein was precipitated by the addition of 300 µL methanol to 100 µL plasma.
Following centrifugation, supernatants (20 µL) were injected
into a Zorbax XDB C8 column (particle size 5 µm, 150×4.6
mm; Agilent, Wilmington, DE, USA), using a mobile phase of
acetonitrile-water-formic acid (75:25:0.2,
v:v:v) with a flow rate of 0.50 mL/min. The column temperature was 25
°C. A Thermo Finnigan TSQ triple quadrupole mass spectrometer equipped
with an electrospray ionization source (San Jose, CA, USA)
was used for the mass analysis and detection.
Quantification was performed using selected reaction monitoring of
the transitions m/z 426 → m/z
175 for domperidone, and m/z 256
→ m/z 167 for the internal standard diphenhydramine,
respectively. The retention times of domperidone and the
internal standard were 3.12 and 3.27 min, respectively.
The response of domperidone were found linear
(r>0.998) over the concentration range of 0.100_100 µg/L, with
the lower limit of quantification of 0.100 µg/L. The intra- and
inter-run precision values for the concentrations of 0.25,
8.00, and 90.0 µg/L were all less than 5.1%, and the accuracy
ranged from 98.9% to 99.4% of the nominal value.
Data analysis Pharmacokinetic parameters were
calculated using standard non-compartmental methods.
Maximum concentration (Cmax) and the time to reach
Cmax (tmax) were determined by the inspection of the plasma
concentration-time curves. The elimination rate constant
(ke) was determined by liner regression of the terminal linear portion of
the ln-concentration-time curve, and the apparent
elimination half-life (t1/2) was calculated as
0.693/ke. The area under the plasma concentration-time curve from 0 to the last point
(AUC0_t) was calculated by the linear trapezoidal method.
The AUC from 0 to infinity (AUC0_∞) was calculated as
AUC0_t+Ct/k
e, where Ct is the last measurable concentration.
The software utilized for the pharmacokinetic analysis was
WinNonlin 5.0.1 (Pharsight, Mountain View, CA, USA).
Statistical analysis The parameters AUC and
Cmax were logarithmically transformed prior to the statistical analysis.
The pharmacokinetic differences (parameters AUC and
Cmax) between administration of domperidone alone and
pretreatment with omeprazole were assessed using a paired
t-test. The differences between free-base and maleate salt
domperi-done were assessed by ANOVA, and 90% confidence
intervals for ratios were given. A Wilcoxon signed rank test was
performed on tmax and
t1/2. For all the analyses,
P<0.05 was considered statistically significant.
Results
Plasma concentration-time curves of domperidone for the
free base and maleate salt tablets administered alone are
shown in Figure 1A. Plasma concentration-time curves for
these 2 tablets administered in the presence of omeprazole
are shown in Figure 1B. The calculated parameters are listed
in Table 1.
For the free-base domperidone, a 16% decrease in
Cmax was observed after pretreatment with omeprazole, compared
with administration alone (P<0.05). The parameter AUC also
decreased, but the change was minor. For maleate salt, with
the exception of a prolonged t1/2
from 7.32 to 9.04 h (P<0.05), no pharmacokinetic parameters were significantly changed.
When domperidone base and domperidone maleate salt
were administered alone, no differences were found in any
parameters between them. In contrast, when they were
administered with omeprazole pretreatment,
Cmax of domperi-done given as the free base was lower (25.9%) than that
given as maleate salt (P<0.05), with a 90% confidence
interval of 66.1%_86.5%. The statistic results are listed in Table 2.
Safety assessment No adverse effects were found
throughout the study. Both domperidone and omeprazole
were well tolerated in all the patients.
Discussion
Increased gastric pH induced by omeprazole
administration is a possible mechanism underlying interactions between
omeprazole and other drugs. By decreasing gastric acidity,
it has the potential to modify the solubility of other drug
substances or alter drug release from products with
pH-dependent dissolution properties. In the present study, we
first compared the relative bioavailability between the free
base and maleate salt of domperidone in healthy patients at
conditions of administration alone or pretreatment with
omeprazole. Similar to the effect of cimetidine combined with
sodium bicarbonate[7], pretreatment with omeprazole does
not lower the absorption of maleate salt. This result
confirms that the absorption of domperidone maleate salt is not
affected by gastric pH environment, and this is a superiority
of its use in clinical therapy.
In this study, we also found that for domperidone base,
in spite of a 16% decrease in
Cmax, the effect of omeprazole on the AUC was minor, much less than that of cimetidine
combined with sodium bicarbonate (a decrease of
>50%)[4,7]. As gastric acidity is a major factor for the absorption of
domperidone base, the difference on increasing gastric pH
might be an explanation. Although gastric pH determination
was not conducted due to the experimental limitation, it has
been reported that treatment of omeprazole may increase
intragastric pH to a range of 5_6 at most in healthy
Helicobacter pylori-negative
patients[8_10]. However, sodium bicarbonate can neutralize intragastric acid to a higher
pH of 6.7[11], nearly a neutral environment where
domperi-done base is practically insoluble. That may be a reason for
the notable effect of sodium bicarbonate. As we can see in
Figure 1B, omeprazole only decreases the rate of absorption
of domperidone base, but does not affect the extent of
absorption. Apparently, there is no clinical significance.
Since omeprazole is known to inhibit cytochrome P450
3A4[12], which is involved in the metabolism of
domperidone[13], it is possible that such an interaction could elevate the
bioavailability of the latter when the 2 agents are
co-administered. However, the present study showed that for
maleate salt, although the elimination half-life was
significantly increased when pretreated with omeprazole, the main
parameter AUC was not increased significantly, and for the
free base, both t1/2 and AUC were unchanged. These results
suggested that there may be an effect, but it is only a slight
one and without any therapeutic consequences.
In conclusion, the study indicates that the absorption of
domperidone as maleate salt is not influenced by the
pre-administration of omeprazole, and the rate, but not the extent
of absorption of the free base, is affected moderately. In this
study, we did not find any clinically relevant interactions
between domperidone and omeprazole. Hence, it has
justified in pharmacokinetics the combination use of these 2 agents
in clinical therapy. Nevertheless, if more effective proton
pump inhibitors are used, domperidone maleate would be
preferable for its better pharmacokinetic characteristics than
that of the free base.
Acknowledgements
We would like to acknowledge Prof Rong-qin LI and the
nursing staff of the People's Hospital of Liaoning Province
for their help in performing the clinical studies. We also
would like to acknowledge Prof Jiang ZHENG (University of
Washington, Seattle, USA) for his help in preparation of the
manuscript.
References
1 Rowland M, Tozer TN. Clinical pharmacokinetics, concepts and
applications. Philadelphia, USA: Lippincott Williams & Wilkins;
1995.
2 Hatlebakk JG, Berstad A. Pharmacokinetic optimisation in the
treatment of gastro-oesophageal reflux disease. Clin
Pharmaco-kinet 1996; 31: 386_406.
3 Huang YC, Colaizzi JL, Bierman RH, Woestenborghs R, Heykants
JJ. Pharmacokinetics and dose proportionality of domperidone
in healthy volunteers. J Clin Pharmacol 1986; 26: 628_32.
4 Barone JA. Domperidone: a peripherally acting dopamine
2-receptor antagonist. Ann Pharmacother 1999; 33: 429_40.
5 Jiang SP, Liang RY, Zeng ZY, Liu QL, Liang YK, Li JG. Effects
of antireflux treatment on bronchial hyper-responsiveness and
lung function in asthmatic patients with gastroesophageal reflux
disease. World J Gastroenterol 2003; 9: 1123_5.
6 Yu HL, Chen XY, Zhong DF. Determination of domperidone in
human plasma by liquid chromatography-tandem spectrometry.
J Instrument Anal 2005; 24 Suppl 5: 149_50 . Chinese.
7 Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS.
Domperidone, a review of its pharmacological activity,
pharmacokinetics and therapeutic efficacy in the symptomatic
treatment of chronic dyspepsia and as an antiemetic. Drugs 1982; 24:
360_400.
8 Gan KH, Geus WP, Lamers CB, Heijerman HG. Effect of
omeprazole 40 mg once daily on intraduodenal and intragastric
pH in H. pylori-negative healthy subjects. Dig Dis Sci 1997; 42:
2304_9.
9 Cederberg C, Rohss K, Lundborg P, Olbe L. Effect of once daily
intravenous and oral omeprazole on 24-hour intragastric acidity
in healthy subjects. Scand J Gastroenterol 1993; 28: 179_84.
10 Hartmann M, Theiss U, Huber R, Luhmann R, Bliesath H, Wurst
W, et al. Twenty-four-hour intragastric pH profiles and
pharmacokinetics following single and repeated oral administration of
the proton pump inhibitor pantoprazole in comparison to
omeprazole. Aliment Pharmacol Ther 1996; 10: 359_66.
11 Graham DY, Opekun AR, Jogi M, Yamaoka Y, Lu H, Reddy R,
et al. False negative urea breath tests with H2-receptor antagonists:
interactions between Helicobacter pylori density and pH.
Helicobacter 2004; 9: 17_27.
12 Li XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of
inhibitory effects of the proton pump-inhibiting drugs omeprazole,
esomeprazole, lansoprazole, pantoprazole, and rabeprazole on
human cytochrome P450 activities. Drug Metab Dispos 2004;
32: 821_7.
13 Simard C, Michaud V, Gibbs B, Masse R, Lessard E, Turgeon J.
Identification of the cytochrome P450 enzymes involved in the
metabolism of domperidone. Xenobiotica 2004; 34: 1013_23.
|
