proton pump inhibitors ( ppis ) potently inhibit gastric acid secretion , and are widely used for prevention and treatment of various acid - related diseases including peptic ulcers and gastro - esophageal reflux diseases .
although their acid inhibitor potency is far stronger than that of histamine h2 receptor antagonists ( h2ras ) , ppis are reported to have some weak points in comparison with those drugs .
a disadvantage of the acid inhibitory effect of ppis is the strong influence of cyp2c19 , a hepatic drug metabolizing enzyme that degrades ppis . in patients with high activity of the cyp2c19 enzyme ( extensive metabolizers ) , the effect of ppi administration is not adequately strong , because of enzymatic degradation . on the other hand , in patients with a low cyp2c19 enzyme activity ( poor metabolizers ) ,
another disadvantage is slow onset of the acid inhibitory effect after ppi administration . to improve these weak points , new types of ppis
rabeprazole is a new type of ppi that is not strongly influenced by cyp2c19 enzyme activity , because it is not mainly degraded by cyp2c19 .
in addition , this drug is reported to inhibit acid secretion more quickly than first generation ppis including omeprazole and lansoprazole .
another agent is esomeprazole , an s - isomer of omeprazole that is a mixture of s- and r - isomers .
esomeprazole has also been reported to not be effectively degraded by cyp2c19 and its effect is not strongly influenced by its enzyme activity .
the acid suppressing effects of rabeprazole ( 20  mg ) and esomeprazole ( 40  mg ) have been investigated , with those of the latter reported to be equal or superior to the former .
the standard doses of rabeprazole and esomeprazole in japan are 10 and 20  mg , respectively , per day .
those ppis at those doses have not been directly compared in regard to quickness of acid inhibition and acid inhibitory potency in cases with different cyp2c19 enzyme activities .
it is considered that intra - gastric ph monitoring soon after acute single administration of a ppi is an ideal experimental design to investigate its quick acid inhibitory effects . in the present study ,
a single standard dose of rabeprazole or esomeprazole was administered to normal volunteers in a multicenter double - blind randomized prospective study with a cross - over design and their effects on intra - gastric ph were compared .
fifty - seven healthy volunteers were enrolled at 9 university hospitals ; shimane university , hokkaido university hospital , gunma university hospital , nippon medical school , yokohama city university hospital , hamamatsu university school of medicine , osaka city university , osaka medical college , and saga medical school .
their mean age was in the 20s and none of the subjects was infected by helicobacter pylori ( h. pylori ) , which was determined by testing for the presence of the h. pylori antibody in serum and urine samples .
the cyp2c19 genotype was tested by a polymerase chain reaction - restriction fragment length polymorphism ( pcr - rflp ) assay , as previously reported .
twenty - nine of the 57 enrolled volunteers were randomly enrolled in the pre - meal ppi administration protocol .
the subjects were investigated by ph monitoring twice , once with 10  mg of rabeprazole and once with 20  mg of esomeprazole .
the ppis were delivered in identical opaque gelatin capsules and discrimination between them was impossible during the study period .
the identical opaque gelatin capsules containing 10  mg rabeprazole or 20  mg esomeprazole were prepared by an author pharmacist ( kn ) and packaged in marked bags , and then delivered to each participating hospital . the key code of the drugs was kept by kn and opened firstly after fixing the final ph data .
the 2 ph monitoring examinations were separated by at least a 1-week interval . an intra - gastric ph monitoring sensor catheter ( zenetics medical , salt lake city , ut )
was introduced into the gastric body and monitoring was started at 17:00 , as previously reported .
a single oral dose of the ppi was administered at 15  min before supper , at 18:45 .
the subjects started eating their supper ( carbohydrates 112.8  g , protein 16.3  g , fat 27.3  g , calories 762  kcal ) at 19:00 and were asked to finish within 30  min .
the subjects were then requested to lie on their bed from 23:00 to 7:00 next morning .
breakfast ( carbohydrates 34  g , protein 5.8  g , fat 2.8  g , calories 85  kcal ) and lunch ( carbohydrates 74.4  g , protein 17.1  g , fat 11.4  g , calories 531  kcal ) were also consumed within 30  min , starting at 8:00 and 12:00 , respectively .
all conditions were the same as above , except that rabeprazole or esomeprazole was administered orally 30  min after the end of supper at 20:00 . in the postprandial administration protocol , the supper ( carbohydrate 52.8  g , protein 8.8  g , fat 9.2  g , calorie 330  kcal ) and breakfast ( carbohydrate 94  g , protein 13.3  g , fat 20.9  g , calorie 617  kcal ) were also slightly different from those used in the pre - meal administration protocol .
median ph for each monitored hour and the percentage of time at which intra - gastric ph was below 4.0 were calculated for the total 24-h period , as well as the daytime ( 7:0023:00 ) and nighttime ( 23:007:00 ) periods .
statistical analysis was performed using a wilcoxon signed rank test when results of a friedman test showed significant differences .
the chronological data shown in fig .  1 , 3 , 4 and 6 were analyzed by linear mixed models .
the sample size of the study was calculated based on the previous studies comparing 40  mg esomeprazole and 20  mg rabeprazole on their first administration day .
calculated the number of necessary subjects as 18 based on parametric assumption and found the statistically significant results in their study .
therefore , in this study , 27 healthy subjects were enrolled in two different protocols ( administration before or after a meal ) .
fifty - seven healthy volunteers were enrolled at 9 university hospitals ; shimane university , hokkaido university hospital , gunma university hospital , nippon medical school , yokohama city university hospital , hamamatsu university school of medicine , osaka city university , osaka medical college , and saga medical school .
their mean age was in the 20s and none of the subjects was infected by helicobacter pylori ( h. pylori ) , which was determined by testing for the presence of the h. pylori antibody in serum and urine samples .
the cyp2c19 genotype was tested by a polymerase chain reaction - restriction fragment length polymorphism ( pcr - rflp ) assay , as previously reported .
twenty - nine of the 57 enrolled volunteers were randomly enrolled in the pre - meal ppi administration protocol .
the subjects were investigated by ph monitoring twice , once with 10  mg of rabeprazole and once with 20  mg of esomeprazole .
the ppis were delivered in identical opaque gelatin capsules and discrimination between them was impossible during the study period .
the identical opaque gelatin capsules containing 10  mg rabeprazole or 20  mg esomeprazole were prepared by an author pharmacist ( kn ) and packaged in marked bags , and then delivered to each participating hospital . the key code of the drugs was kept by kn and opened firstly after fixing the final ph data .
the 2 ph monitoring examinations were separated by at least a 1-week interval . an intra - gastric ph monitoring sensor catheter ( zenetics medical , salt lake city , ut )
was introduced into the gastric body and monitoring was started at 17:00 , as previously reported .
a single oral dose of the ppi was administered at 15  min before supper , at 18:45 .
the subjects started eating their supper ( carbohydrates 112.8  g , protein 16.3  g , fat 27.3  g , calories 762  kcal ) at 19:00 and were asked to finish within 30  min .
the subjects were then requested to lie on their bed from 23:00 to 7:00 next morning .
breakfast ( carbohydrates 34  g , protein 5.8  g , fat 2.8  g , calories 85  kcal ) and lunch ( carbohydrates 74.4  g , protein 17.1  g , fat 11.4  g , calories 531  kcal ) were also consumed within 30  min , starting at 8:00 and 12:00 , respectively .
all conditions were the same as above , except that rabeprazole or esomeprazole was administered orally 30  min after the end of supper at 20:00 . in the postprandial administration protocol , the supper ( carbohydrate 52.8  g , protein 8.8  g , fat 9.2  g , calorie 330  kcal ) and breakfast ( carbohydrate 94  g , protein 13.3  g , fat 20.9  g , calorie 617  kcal ) were also slightly different from those used in the pre - meal administration protocol .
median ph for each monitored hour and the percentage of time at which intra - gastric ph was below 4.0 were calculated for the total 24-h period , as well as the daytime ( 7:0023:00 ) and nighttime ( 23:007:00 ) periods .
statistical analysis was performed using a wilcoxon signed rank test when results of a friedman test showed significant differences .
the chronological data shown in fig .  1 , 3 , 4 and 6 were analyzed by linear mixed models .
the sample size of the study was calculated based on the previous studies comparing 40  mg esomeprazole and 20  mg rabeprazole on their first administration day .
calculated the number of necessary subjects as 18 based on parametric assumption and found the statistically significant results in their study .
therefore , in this study , 27 healthy subjects were enrolled in two different protocols ( administration before or after a meal ) .
of the 57 enrolled subjects , 2 in the preprandial administration group and 1 in the postprandial group were not analyzed because of intolerance to the second ph monitoring examination .
there were no significant differences in regard to gender , age , height , body weight , bmi , and cyp2c19 genotypes between the administration protocol groups ( table  1 ) . when administered before the meal , the median intra - gastric ph after esomeprazole administration tended to be higher than after rabeprazole administration ( fig .  1 ) , whereas intra - gastric ph in the 2:003:00 time period was significantly higher after esomeprazole administration .
we also calculated percent time of intra - gastric ph > 4.0 over the 24-h period , as well as during the daytime and nighttime periods .
again , esomeprazole tended to show a stronger acid inhibitory effect , though differences with rabeprazole were not significant ( fig .  2 ) .
when the data was separately calculated for different cyp2c19 genotypes , esomeprazole raised intra - gastric ph more effectively in rapid metabolizers at 4 time points in 24-h observation period ( fig . 
3 ) , while there was no apparent difference between intra - gastric ph between rabeprazole and esomeprazole in the intermediate and poor metabolizers , except at a single time point in poor metabolizers .
when the ppis were administered after meals , there were no apparent differences in median intra - gastric ph at any time point after either administration ( fig . 
4 ) . furthermore , after calculating percent time of intra - gastric ph > 4.0 , there were no differences found during the daytime and nighttime periods ( fig .  5 ) .
median intra - gastric ph was also calculated based on cyp2c19 genotype , and compared between rabeprazole and esomeprazole , with no significant difference found , except at a single time point in poor metabolizers ( fig . 
the present results show that the acid inhibitory effects of 10  mg of rabeprazole and 20  mg of esomeprazole after single oral doses were similarly potent , especially when administered after meals .
four kinds of ppis , omeprazole , lansoprazole , rabeprazole , and esomeprazole , are available for clinical practice in japan , which can be divided into 2 groups based on their degradability by the hepatic drug metabolizing enzyme cyp2c19 .
omeprazole and lansoprazole are easily degraded by cyp2c19 , while rabeprazole and esomeprazole are not .
asian individuals are known to have heterogeneous cyp2c19 enzyme activity , as 30% are extensive metabolizers with high enzyme activity , 20% are poor metabolizers with low enzyme activity , and the remaining 50% are intermediate metabolizers .   therefore , different from western countries , the acid inhibitory effects of omeprazole and lansoprazole
are known to be diverse among individuals . in cases with a high level of cyp2c19 enzyme activity
, the acid inhibitory effects of these drugs are expected to be limited . to improve uncertainty , the more stable ppis rabeprazole and esomeprazole
are increasingly used in clinical practice for japanese patients , with standard oral doses of 10 and 20  mg , respectively .
rabeprazole is a newly developed racemic mixture compound reported to resist cyp2c19 degradation , while esomeprazole is an s - isomer of omeprazole and similarly resistant to cyp2c19 .
therefore , these ppis are considered to have a more consistent acid inhibitory effect irrespective of cyp2c19 enzyme activity . however , that of esomeprazole is considered to become submaximal when the drug is administered after a meal .
there are 2 possible mechanisms regarding this weak point of esomeprazole to consider , decreased absorption and incomplete activation .
the plasma concentration of esomeprazole was investigated and compared when administered during fasting and after meals .
those results clarified that the plasma concentration of esomeprazole was higher when administered during fasting , though the precise mechanism related to that difference is not clear .
all ppis need to be activated by the acidic environment in the secretory canaliculi of parietal cells .
when administered after meals , an absorbed ppi will not be effectively activated because food - induced acid secretion and the highly acidic environment in the secretory canaliculi are nearly terminated when the plasma concentration of the drug reaches a peak level at 23  h after administration . mainly based on data obtained from esomeprazole trials in western countries , ppis
are recommended to be administered 30  min before meals . on the other hand ,
the acid inhibitory effect of rabeprazole was shown to be not significantly influenced by timing of administration . in the present study , intra - gastric acidity after a single postprandial oral dose of rabeprazole ( 10  mg ) or esomeprazole ( 20  mg ) was similarly raised and remained nearly identical for 24  h. on the other hand , the acid inhibitory effect of the latter was slightly stronger than that of the former when each was administered before meals , though the difference was not statistically significant .
these results confirm a previous report showing that esomeprazole had a stronger acid inhibitory effect when administered 30  min before meals . in the present study ,
direct comparisons of the acid inhibitory effects of the tested ppis between pre- and post - prandial administrations was difficult , since the foods taken during the monitoring periods were not identical .
however , when we compared the pre- and post - prandial administrations , esomeprazole was stronger with pre - prandial administration , as previously reported , while rabeprazole was equally potent irrespective of the timing of administration . in japan ,
approximately 80% of physicians instruct their patients to take ppis after breakfast and approximately 10% after dinner . therefore , 90% of the patients take ppis after meals . in such an environment ,
the acid inhibitory effects of the present ppi administrations are considered to be nearly identical , though esomeprazole may show a statistically non - significant benefit when administered before meals .
the first is lack of baseline intra - gastric ph data obtained without any drug administration . to more sensitively check the potency of any acid inhibitory effect , baseline ph data are necessary
therefore , a comparison of the intra - gastric ph observed after rabeprazole and esomeprazole administrations is the only one possible in this study .
therefore , we could not correlate the pharmacokinetic disposition of ppi with the intragastric ph .
the influence of meal on the absorption of ppis and their acid inhibitory effects could not be made clear .
another is the lack of ph data during chronic administration of the ppis , since these drugs are frequently used for chronic treatment .
an additional study with chronic administrations of ppis as well as baseline data may be necessary in the future . in summary , we found that the intra - gastric ph values for 24  h after a single oral dose of rabeprazole ( 10  mg ) or esomeprazole ( 20  mg ) were nearly identical , especially when administered after meals . on the other hand
the center for clinical research and the first department of medicine at hamamatsu university school of medicine have received grants from takeda pharmaceutical co. , ltd . , astrazeneca kk , eisai co. , ltd . , daiichi - sankyo co. , ltd . , and
sugimoto m and furuta t have received lecture fees from takeda pharmaceutical co. , ltd . ,
astrazeneca kk , eisai co. , ltd . , daiichi - sankyo co. , ltd .
kusano m received lecture fee and research grant from eisai co. , ltd . , and lecture fee from astrazeneca kk and daiichi - sankyo co. , ltd .
, takeda pharmaceutical co. , ltd . , and astrazeneca kk and received research funds from eisai co. , ltd . , takeda pharmaceutical co. , ltd . , otsuka pharmaceutical co. , ltd . , astrazeneca kk , astellas pharmaceutical co. , ltd . , and daiichi - sankyo co. , ltd .
higuchi h and fujimoto k received research grant and lecture fees from astrazeneca kk , eisai co. , ltd . , daiichi - sankyo co. , ltd .
naora k received research grants from astrazeneca kk , eisai co. , ltd . , and takeda pharmaceutical co. , ltd .
arakawa t received research grant from eisai co. , ltd . and otsuka pharm co. , and lecture fee from eisai co. , ltd .
kinoshita y received research grants and lecture fees from astrazeneca kk , eisai co. , ltd .
 comparisons between the acid inhibitory effects of rabeprazole and esomeprazole after single oral administration with standard doses have not been previously presented . 
 we examined intra - gastric ph after oral administrations of these two proton pump inhibitors using 24-h ph monitoring . 
 fifty - four normal volunteers not infected by helicobacter pylori were investigated . using a cross - over design , we administered 10  mg of rabeprazole or 20  mg of esomeprazole in 27 at 30  min after supper and in the remaining 27 subjects at 15  min before supper , and performed 24-h ph monitoring . 
 intra - gastric ph data were nearly identical when the proton pump inhibitors were taken after meals . even if the data were compared in different cyp2c19 genotypes , rabeprazole and esomeprazole did not show the difference . in poor metabolizer , both of the drugs showed stronger acid inhibition . when taken before meals , intra - gastric ph after esomeprazole administration was slightly but not significantly higher than that observed after rabeprazole administration not only in daytime but also in nighttime period . in conclusion , rabeprazole and esomeprazole were similarly effective when administered after a meal . 
Introduction
Materials and Methods
Subjects
pH monitoring
Statistical analysis
Results
Discussion
Conflicts of Interest