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Relative bioavailability of omeprazole capsules after oral dosing

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Omeprazole, a proton pump inhibitor, effectively suppresses the gastric acid secretion in the parietal cells of stomach. Pharmacokinetics and relative bioavailability of generic products of omeprazole were compared with innovator product, Losec. Twelve healthy adult volunteers participated in the study which was conducted according to a randomized, open-label single dose Latin square cross over design. The preparations were compared using area under the plasma concentration - time curve (AUC), peak plasma concentration (Cmax), and time to reach peak plasma concentration (tmax). The two generic capsules proved to be bioequivalent with brand-name omeprazole with regard to the pharmacokinetic parameters Cmax, AUC0-t, AUC 0-inf and tmax. Moreover the parametric confidence intervals (90%) for the ratio of the Cmax, AUC0-8 and AUC0-∞ values lie between 0.8-1.2. The test formulations were found bioequivalent to the reference formulation by the one-way ANOVA test procedure. On the basis of these results, the 3 formulations were considered to be bioequivalent. Two subjects demonstrated increase in AUCs and high C max after administration of either product which may attribute to the ethnic disposition of omeprazole in these subjects.
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DARU Volume 12, No. 4, 2004 146
RELATIVE BIOAVAILABILITY OF OMEPRAZOLE CAPSULES
AFTER ORAL DOSING
SAYED ABOLFAZL MOSTAFAVI, NASER TAVAKOLI
Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical
Sciences, Isfahan, Iran
ABSTRACT
Omeprazole, a proton pump inhibitor, effectively suppresses the gastric acid secretion in the parietal cells
of stomach. Pharmacokinetics and relative bioavailability of generic products of omeprazole were
compared with innovator product, Losec. Twelve healthy adult volunteers participated in the study which
was conducted according to a randomized, open-label single dose Latin square cross over design. The
preparations were compared using area under the plasma concentration – time curve (AUC), peak plasma
concentration (Cmax), and time to reach peak plasma concentration (tmax). The two generic capsules proved
to be bioequivalent with brand-name omeprazole with regard to the pharmacokinetic parameters Cmax,
AUC0-t, AUC0-inf and tmax. Moreover the parametric confidence intervals (90%) for the ratio of the Cmax,
AUC0-8 and AUC0- values lie between 0.8-1.2. The test formulations were found bioequivalent to the
reference formulation by the one-way ANOVA test procedure. On the basis of these results, the 3
formulations were considered to be bioequivalent. Two subjects demonstrated increase in AUCs and high
Cmax after administration of either product which may attribute to the ethnic disposition of omeprazole in
these subjects.
Keywords: Omeprazole, Bioequivalence, Pharmacokinetics, Ethnic Disposition
INTRODUCTION
Omeprazole, a gastric acid pump inhibitor which
has greater anti-secretary activity than histamine
H2 receptor antagonists has been widely used in
the treatment of reflux oesophagitis, Zollinger–
Ellison syndrome and peptic ulcer disease (1,2). In
order to prevent degradation of drug in acid media,
the drug is formulated as enteric-coated granules in
capsule forms. Differences in the quality of the
granules coating are a potential limiting factor for
in vivo performance of the product and various
product may cause different bioavailability
parameters. Furthermore, the mean time to attain
maximum plasma concentrations (tmax) of
omeprazole is highly formulation dependent (3). It
is a very well tolerated drug and its doses are 20
mg up to 80 mg (4). Omeprazole terminal half-life
is between 0.5 and 2 hours (5-8). Although
omeprazole is well absorbed from the
gastrointestinal tract, its oral bioavailability in
humans is about 40 to 50% suggesting pronounced
first pass metabolism for this drug (4).
Omeprazole is eliminated rapidly and almost
completely by liver metabolism. After absorption,
it is metabolized and 3 main metabolites;
omeprazole sulphone, omeprazole sulphide and
hydroxy omeprazole have been identified in
human plasma (8-10). Hydroxylation of
omeprazole at the 5-position is subject to genetic
polymorphism and the sulphone in plasma is
cumulated in poor metabolizers of S-mephenytion
4’ hydroxylation (11). Therefore, the majority of
individuals metabolize the drug normally, and only
a small number might be expected to be poor
metabolizer (11). Clinical experiences with
omeprazole has been gained for more than 20
years of its clinical use (1,2,4, 5,8,12,13). Various
studies have investigated the pharmacokinetic
properties of omeprazole (1-5,11-13), however
increasing requirements for proof of
pharmacokinetic data make new studies mandatory
to confirm earlier findings according to today’s
standards. Thus, the aim of this study was to
determine pharmacokinetics and relative
bioavailability of omeprazole in man following
oral administration of omeprazole enteric-coated
granules in capsules.
MATERIALS AND METHODS
Commercial oral dosage forms of omeprazole
20mg enteric coated granules in capsule were
provided by two Iranian pharmaceutical
manufacturing companies, Abidi (omeprazole) and
lorestan (lorsec). Losec®, a reference product, was
bought from astra Sweden. Omeprazole powder
was provided by the Abidi Pharmaceutical Co.
Flunitrazepam was a gift from the pharmacology
laboratory of our faculty. All other chemicals and
reagents were HPLC or analytical grade.
Correspondence: Sayed Abolfazl Mostafavi, Faculty of Pharmacy & Pharmaceutical Sciences, Isfahan University of
Medical Sciences, Isfahan, Iran, Email: mostafavi@pharm.mui.ac.ir
Relative bioavailability of omeprazole 147
Table 1. Pharmacokinetic parameters of omeprazole in ten normal metabolizer of omeprazole (mean± S.D.)
Treatment Cmax
(ng/ml) Tmax
(h) AUC0-8
(ng.h/ml) AUC0-inf
(ng.h/ml) T1/2
(h)
Omeprazole 283 ± 113 1.75 ± 0.63 455 ± 155 481 ±175 2.04 ± 0.82
Lorsec® 276 ± 94 2.40 ± 0.88 489 ± 180 503 ± 175 1.82 ± 0.68
Losec® 284 ± 105 1.60 ± 0.57 461 ± 171 487 ± 161 1.96 ± 0.71
CI for Omeprazole 0.86-1.17 N.R 0.88-1.11 0.87-1.13 N.R
CI for Lorsec® 0.86-1.14 N.R 0.99-1.15 0.95-1.13 N.R
CI = 90% Confidence Interval, NR = Not Required, Cmax = Maximum plasma concentrations, Tmax = Time required to reach the
maximal concentrations, AUC0-8 = AUC until last quantified sample using the trapezoidal rule, AUC0-inf = The total AUC until
infinity, T1/2 = Terminal half life
Table 2. Pharmacokinetic parameters of omeprazole in subjects 7 and 9.
Cmax
(ng/ml) Tmax
(h) AUC0-8
(ng.h/ml) AUC0-inf
(ng.h/ml) T1/2
(h)
Treatment 7 9 7 9 7 9 7 9 7 9
Omeprazole 676 923 4 3 2597 1720 4853 1930 4 1.5
Lorsec® 628 457 3 4 2793 1032 4848 1050 5 1.2
Losec® 991 899 1 1.5 3876 2075 4685 2125 3 1.4
Cmax = Maximum plasma concentrations, Tmax = Time required to reach the maximal concentrations, AUC0-8 = AUC until last
quantified sample using the trapezoidal rule, AUC0-inf = The total AUC until infinity, T1/2 = Terminal half life
Study design
The study was based on a single-dose, Latin square
cross over design under fasting condition. After an
overnight fasting (for 10 hours) subjects were
given one capsule of either product followed by
250 ml of water. They were fasted over 3 hours
post-doses and then they received the same
breakfast and lunch according to the time
scheduled. Therefore, all subjects received
equivalent of 20 mg omeprazole on three
occasions separated by a 7 days wash out period.
Volunteers
Twelve healthy Iranian male subjects participated
in the study. The ages of subjects were between 22
and 24 years (mean age ± SD, 23.6 ± 0.7 years).
The average body weight was 76.25 ± 8.4 kg
(range 62.0 – 87.0kg) and the average height was
178.5 ± 3.68 cm (range 172-186 cm). Prior to
inclusion into the study, written informed consent
of each subject was obtained. The purpose, the
nature of the study and any possible risks were
explained and it was made clear, that any subject
may withdraw voluntarily from the study at any
time without prejudice. Before the beginning of
the trial a detailed medical and clinical-chemical
examination of all volunteers was carried out,
which revealed normal finding in all examination.
Twelve hours before medication and during the
study, all subjects abstained from caffeine
containing foods and drinks, and nicotine. No
medication was allowed one week before and
during the study.
Blood sampling
10 ml blood samples were taken from a cubical
vein into heparinized tubes at the following time
points: 0 h (prior to administration), and at 0.5,
0.75, 1, 1.5,2, 2.5, 3, 4, 5, 6, 8 hour following
dosing. Blood samples were centrifuged within 15
min and the plasma stored at - 20ºC until analyzed.
Omeprazole analysis
Analysis of omeprazole in plasma was performed
using a validated high performance liquid
chromatographic assay (6) with some
modifications. To 1ml of the plasma sample was
added, 100 µl of methanol: acetate buffer (pH=9.6)
(1:4v/v) and after mixing with 5ml of
dichloromethane: acetonitrile (4:1v/v) it was
vortexed for 30 seconds. Following centrifugation
at 2000g for 10 min, 4 ml of the organic phase was
separated and evaporated under a nitrogen stream.
The residue was dissolved in 200µl of mobile
phase, and 100 µl was injected into the HPLC
system consisting of a reversed-phase. Nova-pack
C8 (15cm x 3.0mm, 4µm, waters), column which
was maintained at room temperature. The UV
detector was set at 302 nm. The mobile phase was
a mixture of methanol: acetonitrile: phosphate
Mostafavi et al 148
buffer (pH 7.2) (40:8:52,v/v) and was pumped at a
flow rate of 1ml/min. Quantitation was obtained by
calculation of the peak area ratio of omeprazole to
the internal standard. The values of coefficient
variation were 3.15% at 100 ng/ml and 3.99% at
10 ng/ml (n=9). The lower limit of quantitation
was 5 ng/ml.
Pharmacokinetic data analysis
The AUC was calculated by the linear trapezoidal
rule. The area from the last concentration point
(Clast) to infinity was calculated as C last/β, where β
was the terminal elimination rate constant
calculated by regression through at least three data
points in the terminal elimination phase. The
terminal elimination half-life (t½) was calculated
by 0.693/ β. Maximum plasma concentrations
(Cmax) and the time required to reach the maximal
concentrations (tmax) were obtained directly from
plasma concentrations versus time curve of each
individual volunteers.
Statistical analysis
Pharmacokinetic variables and bioequivalence
metrics from each study were compared using
analysis of variance (ANOVA). The ANOVA
model included sequence, subject nested within
sequence, phase and treatment (omeprazole,
lorsec® and losec®) as factor. After logarithmic
transformation Cmax, AUC0-t, and AUC0- were
analyzed according to the current FDA guidelines
(14). The 90% confidence interval of the ratio of
the test / reference (T/R) was calculated according
to the reported methods (15,16). In all tests, a
probability level of significance preset at α = 0.05.
All statistical analysis was performed using SPSS
10.
RESULTS
Inspection of the omeprazole pharmacokinetic data
revealed that subjects 7 and 9 eliminated
omeprazole slowly. Therefore, the data of these
subjects were excluded from the statistics and are
presented separately. The pharmacokinetic results
of three different oral formulations of omeprazole
are summarized in table 1.
Figure 1 depicts the mean plasma concentrations
of the group of 10 subjects with normal metabolic
status. Fig 2 and 3 show the plasma concentrations
of subjects 7 and 9. The 90% confidence intervals
of Cmax, AUC0-t, AUC0- are summarized in table 1
as well. After administration of the test products,
peak plasma concentrations of 283 ± 113 and 276±
94 ng/ml were obtained for omeprazole and lorsec
formulations respectively. The corresponding
value after administration of the reference capsule
(Losec®) was 284 ± 105. The statistical analysis
did not show any significant differences for Cmax in
three formulations. The 90% confidence intervals
of this value were in the ranges 0.86-1.17% for
omeprazole and 0.86-1.14 for lorsec respectively.
The AUC0- was calculated to be 481 ± 175
ng.h/ml for omeprazole, 503 ± 175 ng.h/ml for
lorsec and 487 ± 161 ng.h/ml for losec. The
estimated relative bioavailability amounted to 1 ±
0.2 % and 1.04 ± 0.25% for omeprazole and
Lorsec® respectively. Statistical analysis showed
equivalency of both dosage forms with the 90%
confidence interval of 0.87-1.13 for omeprazole
and 0.95-1.13 for Lorsec. Similar finding were also
observed for AUC0-t (omeprazole 455 ± 155
ng.h/ml, Lorsec 489 ± 180 ng.h/ml, and losec 461
± 171), relative bioavailability and 90%
confidence intervals for omeprazole and Lorsec®
respectively. The AUC0- and AUC0-t for the three
products were not statistically different (p> 0.05).
0
50
100
150
200
250
02468
Time (h)
Concentrations, ngml-1
Omeprazole
Losec
Lorsec
Fig. 1. Omeprazole plasma concentrations in 10 normal
metabolizers following single oral administration of 20
mg omeprazole in enteric coat granulated capsules.
After log transformation of AUC and Cmax no
statistical significant were found. A statistically
significant difference was observed between the
Tmax values (p <0.044) of the two products. The
terminal half-life was not different in these
products significantly.
DISCUSSION
The aim of the present study was to assess the
relative bioavailability of two enteric-coated
granulated omeprazole capsules in comparison to a
reference product, Losec®.
The plasma levels and pharmacokinetic data
revealed that two subjects (7 and 9) may be poor
metabolizers of omeprazole as the AUC were
approximately 2-6 times greater in these subjects.
The pharmacokinetic data of these subjects were
therefore excluded from the biometrical analysis
and are discussed separately (Table 2).
Omeprazole was safe and well tolerated by all
subjects. None of the subjects reported any adverse
events that could be related to the medication. It
should be emphasized that subjects 7 and 9 did not
Relative bioavailability of omeprazole 149
Subject 7
0
200
400
600
800
1000
1200
02468
Subject 9
0
200
400
600
800
1000
02468
Time (h)
Concentrations, ngml-1
Omeprazol
Losec
Lorsec
Time (h)
Concentrations, ngml-1
Omeprazol
Losec
Lorsec
Fig. 2. Omeprazole plasma concentrations in subject 7
following single oral administration of 20 mg
omeprazole in enteric coat granulated capsules.
experience any adverse drug reactions during the
study.
The AUC0-t and AUC0- for the three products
were not statistically different (p>0.05) suggesting
comparable plasma profiles for these products.
After log transformation, ANOVA showed no
statistical differences between three formulations
as well. The statistical analysis did not show any
considerable differences in periods, formulations
or sequences (p>0.05). On the basis of Cmax,
AUC0-t, and AUC0-, the capsules fulfilled the
formal criteria for bioequivalency to the reference
product. For AUC0-, the treatment ratio were
estimated to be 1 ± 0.2 % and 1.04 ± 0.25% for
omeprazole and lorsec respectively, indicating
complete bioavailability of omeprazole from the
test products in comparison to the registered
product losec®. Similar results were obtained for
AUC0-t of the treatment ratio. Tmax demonstrated
the expected delay of the absorption from the
enteric-coated granulated capsules. A statistically
significant difference were observed between the
Tmax values (p <0.044), although from the
therapeutic point of view the slight differences
may not be significant or important. The
pharmacokinetic findings in this study are well in
agreement with published data for earlier trials
(2,17). Although in other investigations (17) the
confidence interval of Cmax for their products fell
outside the FDA accepted range (0.8-1.25%).
These values in our study were between the
accepted ranges. The differences that they have
found in Cmax may be the results of having some
subjects who are poor metabolizes since these
authors did not exclude them from their data. The
disposition kinetic of omeprazole has been studied
specifically in extensive and poor metabolizers of
S-mephenytion and pronounced inter-phenotypic
differences (P<0.001) between the two groups with
Fig. 3. Omeprazole plasma concentrations in subject 9
following single oral administration of 20 mg
omeprazole in enteric coat granulated capsules.
regard to the mean kinetic parameters of
omeprazole including Tmax has been described.
Furthermore, it is reported (11) that the t1/2 and
mean AUC value were approximately 3 times
longer and 10 times greater in poor metabolizers
than in extensive metabolizers. The deficient
metabolizers are known to build up high plasma
concentrations over longer periods of time, and
have increased elimination half-lives and Tmax.
Our results showed that the mean AUC values
were approximately 2-6 times greater in two
subjects. The half-life of omeprazole however was
not different in these subjects which might be due
to the time of sample collection since samples
were taken only for 8 hours.
The findings that two subjects out of twelve
Iranian volunteers might be poor metabolizers of
omeprazole is somewhat surprising, since it is well
known that the frequency of occurrence of the poor
metabolizer phenotype of S-mephenytoin is much
greater (17-23%) in oriental (18-20) than that of
Caucasian (3-6%) populations (21-23). This might
be due to the number of subjects that participated
in this study.
In conclusion, the pharmacokinetic results of this
study confirm earlier findings and demonstrate
complete bioavailability of the marketed capsules
compared to the reference product. The results of
this study also emphasize that it is advisable to
assess the metabolic status by phenotyping
subjects with an adequate test prior to conducting
pharmacokinetic studies.
ACKNOWLEDGMENT
The author would like to acknowledge Abidi and
Lorestan Pharmaceutical companies for their
financial supports.
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European data on the polymorphic metabolism of debrisoquine, sparteine, dextromethorphan and mephenytoin have been collected. No significant difference in phenotype frequencies was found between the separate series for debrisoquine, sparteine and dextromethorphan, which supports the claim that these probe drugs reflect the same enzyme polymorphism. The mean frequency of the phenotype slow debrisoquine metaboliser was 7.65% based on 5005 determinations. The overall mean reflecting all three drugs and 8764 determinations was 7.40%. This is consistent with a gene frequency of 0.27 (95% confidence interval 0.26–0.28). The overall mean of the phenotype slow metaboliser of mephenytoin was 3.52% corresponding to a gene frequency of 0.19 (confidence interval 0.17–0.20). The incidence of slow metabolism of debrisoquine and possibly also of S-mephenytoin was homogeneous in the samples from European populations. This is of considerable interest as interethnic differences are now being found both in the phenotypic characters as well as the genotypes of polymorphic drug oxidation.
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Because of the large interethnic differences in the incidence of poor metabolizer phenotypes, French Caucasians have been studied for two independant polymorphisms, debrisoquine/dextromethorphan and mephenytoin metabolism. One hundred and thirty-two unrelated French Caucasians were phenotyped using oral doses of dextromethorphan 20 mg and mephenytoin 100 mg. Individual dextrorphan excretion over 8 h and the dextromethorphan/dextrorphan metabolic ratio were calculated. Extensive metabolizers were taken as subjects with a high dextrorphan output (15.56 µmol/8 h) and a low metabolic ratio (0.0023), and poor metabolizers were those with a low dextrorphan output (0.39 µmol/8 h) and a high metabolic ratio (7.00). Individual 4-hydroxymephenytoin excretion and mephenytoin hydroxylation indices were also determined. Extensive metabolizers eliminated large amounts of 4 hydroxymephenytoin (133.2 µmol/8 h) and had a hydroxylation index of 1.99, and poor metabolizers, because of impaired mephenytoin metabolism, had a high hydroxylation index (277). The incidence of the poor metabolizer phenotype was 3% for dextromethorphan (95% confidence limits 0.5%–8.5%) and 6% for mephenytoin (95% confidence limits 2%–12.5%).
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Omeprazole is a substituted benzimidazole derivative which markedly inhibits basal and stimulated gastric acid secretion. It has a unique mode of action, irreversibly blocking the so-called proton pump of the parietal cell which is supposedly the terminal step in the acid secretory pathway. In animals, on a weight basis, omeprazole is 2 to 10 times more potent than cimetidine in inhibiting gastric acid secretion. Toxicological studies in rats have shown that very high doses of omeprazole administered for 2 years produce hyperplasia of gastric enterochromaffin-like cells and carcinoids, a few with proliferations into the submucosa. The significance of such findings to the clinical situation is wholly speculative and requires further research. Preliminary studies in patients with duodenal ulcers or Zollinger-Ellison syndrome have found no mucosal changes which would suggest that the drug represents a risk for development of carcinoid tumours at therapeutic dosages. In patients with duodenal ulcers omeprazole, at dosages of at least 20mg once daily, produced ulcer healing rates of between 60 and 100% after 2 weeks and between 90 and 100% after 4 weeks, even in patients resistant to treatment with H2-receptor antagonists. Comparative trials clearly demonstrated that omeprazole 20 to 40 mg administered once daily was significantly more effective than usual dosage regimens of cimetidine and ranitidine in healing duodenal ulcers during 2 to 4 weeks of treatment. At present no data are available evaluating omeprazole as maintenance therapy once ulcers have healed. Other clinical trials have also shown that omeprazole is effective for treating gastric ulcers, ulcerative peptic oesophagitis, and Zollinger-Ellison syndrome. In patients with Zollinger-Ellison syndrome the profound and long lasting antisecretory activity of omeprazole may make it the drug of choice for treating the massive acid hypersecretion associated with the disease, especially when H2-receptor antagonists are ineffective. During clinical trials reported to date omeprazole has been very well tolerated but further clinical experience is essential to fully evaluate its safety profile. Thus, omeprazole represents a pharmacologically unique antisecretory drug which is very effective for rapidly healing peptic ulcers and peptic oesophagitis, and for reducing gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. If the apparent absence of undesirable mucosal morphological changes during treatment with usual doses in patients with peptic ulcer disease is confirmed, it may be a major advance in the treatment of these diseases.
The pharmacokinetics of omeprazole have been studied to varying extent in the mouse, rat, dog and in man. The drug is rapidly absorbed in all these species. The systemic availability is relatively high in the dog and in man provided the drug is protected from acidic degradation in the stomach. In man the fraction of the oral dose reaching the systemic circulation was found to increase from an average of 40.3 to 58.2% when the dose was raised from 10 to 40 mg, suggesting some dose-dependency in this parameter. The drug distributes rapidly to extra-vascular sites. The volume of distribution, V beta, in man is comparable to the volume of the extracellular water. The penetration into the red cells is low, the ratio between the concentration in whole blood and in plasma being about 0.6. Omeprazole is bound to about 95% to proteins in human plasma. The binding is lower in the dog and rat (90 and 87%, respectively). Omeprazole is eliminated almost completely by metabolism and no unchanged drug has been recovered in the urine in the species studied. Two metabolites, characterised as the sulfone and sulfide of omeprazole, have been identified and quantified in human plasma. The mean elimination half-life in man and in the dog is about 1 hour, whereas half-lives in the range of 5 to 15 minutes have been recorded in the mouse. In two studies in man, the mean total body clearance was 880 and 1097 ml X min-1, indicating that omeprazole belongs to the group of high clearance drugs. In the dog, too, the drug appears to be rapidly cleared from the blood, the mean total body clearance being about 10.5 ml X min-1 X kg-1. In the rat and dog, 20 to 30% of an i.v. or oral dose of omeprazole is excreted as metabolites in the urine and the remaining fraction is recovered in the faeces within three days after the administration. In man, the excretion of radioactivity via the kidneys is much more efficient and the recoveries in the excreta are approximately the reverse of those in the rat and dog. In vitro studies with rat liver microsome preparations suggest that omeprazole and cimetidine inhibit cytochrome P-450-mediated metabolic reactions to about the same extent in equimolar concentrations. However, since the molar daily dose of cimetidine will be 25 to 50 times higher than that of omeprazole, the latter might have less influence on the mixed function oxidase system than cimetidine.(ABSTRACT TRUNCATED AT 400 WORDS)