animal pharmacodynamics of omeprazole. a survey of its pharmacological properties in...
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Animal pharmacodynamics of omeprazole. A survey of its pharmacological properties in vivo LARSSON H, MATTSON H, SUNDELL G, CARLSSON E. Department of Gastrointestinal Pharmacology, AB Hassle, Molndal, Sweden.
Larsson H, Mattsson H, Sundell G, Carlsson E. Animal pharmacodynamics of omeprazole. A survey of its pharmacological propertis in vivo. Scand J Gastroenterol 1985;2O(suppl 108):23-35.
In the present paper, a collection of experimental data is presented describing the phar- macological profile of omeprazole mainly in dogs and rats.
Omeprazole potently inhibited gastric acid secretion in different experimental models. In the dog, for instance, omeprazole was 2-7 times more potent than cimetidine, depending on the route of administration, and in the rat the difference was even greater. Omeprazole was equally potent against different types of stimulation, whereas cimetidine was not, in- dicating differences in their mechanisms of action.
In the dog, the duration of the antisecretory effect was long and lasted for 3-4 days after a single maximal dose of omeprazole. The inhibitory effect after repeated, daily ad- ministration of submaximal doses therefore gradually increased and attained a steady- state level after five doses. Treatment up to one year with very high oral doses did not af- fect the duration of effect. During long-term treatment with high doses of omeprazole a 10-fold increase in meal-stimulated plasma gastrin levels was recorded. This was probably due to a nearly complete inhibition of acid secretion over 24 hours during the study. The gastrin values returned to control levels within eight days after the end of the treatment.
Omeprazole was rapidly absorbed (peak plasma levels were reached within one hour) and theelimination half-life was approximately one hour. In the dog, thegastric antisecretory effect was related to the total dose and the area under the plasma concentration curve, whereas the peak level or the shape of the curve was of minor importance.
Omeprazole, given orally to rats, dose-dependently prevented experimentally induced gastric lesions. Neither inhibition of acid secretion, stimulation of gastric bicarbonate secretion nor interference with the synthesis of endogenous prostaglandins seems to be of any great importance for the gastric protective effect of omeprazole.
Omeprazole seems to be very specific in its gastric acid antisecretory and gastric protec- tive actions since, apart from a decrease in the rate of gastric emptying found after very high oral doses in the rat, no other general pharmacological effects of omeprazole have been observed. Thus, omeprazole was devoid of histamine H,-receptor blocking proper- ties, did not affect the intestinal transport rate, pancreatic secretion, autonomic control of the cardiovascular system or kidney excretion of hydrogen ions.
Key-words: Omeprazole; dog; rat; gastric acid secretion; pharmacokinetics; duration of action; repeated administration; gastrin; gastric mucosal protection; general phar- macology.
Larsson Hbkan, Ph.D., Dept. of Gastrointestinal Pharmacology, AB Hassle 5-431 83 Molndal, Sweden.
Introduction longacting inhibitor of gastric acid secretion. This work has resulted in a new class of antisecretory
For several years, our research activity has been agents, the substituted benzimidazoles. Their focused on developing a specific, potent and mechanism of action represents a new principle, as
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they interact with the gastric H’K’ATPase, the en- zyme constituting the final step in the formation of gastric acid.
This specific inhibitory action on the “proton pump” offers a unique and highly selective means of controlling acid secretion, both as a tool in gastrointestinal research and in the therapy of pep- tic ulcer.
.4mong the substituted benzimidazoles, omeprazole has been extensively studied in various experimental animal models. In the present report, the pharmacodynamic properties of omeprazole are surveyed. The gastric acid antisecretory proper- ties, i.e., potency against various secretagogues after various routes of administration and duration of effect following both single and reDeated ad-
Acid output mmol H’ lh
- I
ministration, have been evaluated in animal ex- periments. The H,-receptor antagonist cimetidine has been used as a reference compound in many ex- periments.
Other possible effects of omeprazole on the gastrointestinal tract have been studied, i.e., gastric mucosal protective properties, effects on gastric secretion of pepsin and bicarbonate, motility and pancreatic secretion.
General pharmacological studies concerning the function of other organ systems have also been per- formed. These include studies on cardiovascular and kidney functions, and are discussed in relation lo the specificity in the action of omeprazole.
Gastric antisecretory effects in the conscious dog and rat Relation of antisecretory effect to route of administration and to stimulus of acid secretion In a comparative study using either chronic gastric fistula dogs or Heidenhain pouch dogs, gastric acid secretion was submaximally stimulated with either histamine or pentagastrin (1). Adminisiration of omeprazole or cimetidine produced a dose-related
-1 0 1 2 3 h Time t
i.d. adm
Figure 1. Gastric fistula dog. Antisecretory effects of omeprazole (0.5 pmol/kg, ), cimetidine (4 qnol/kg, A) and placebo (0) given intraduodenally at t = 0 on histamine-stimulated (100-200 nmol x kg-’) x h-’ acid secretion. M e a n f S E M , n=4).
Omeprazole was found to be the most potent in- hibitor. After i.d. administration, ED,,-values of 0.26 and 0.56pmoVkg were recorded on histamine- and pentagastrin-stimulated acid secretion, respec- tively (Table I). Cimetidine was less potent with ED,,-values of 1.83 and 3.87pmol/kg, respectively. For both compounds there was a linear relationship between the decrease of volume secretion and acid output.
The ED,,-value of omeprazole after i.v. injection was 0.35 pmol/kg on histamine-stimulated acid secretion, which is not significantly different from that found after i.d. administration (Table I).
Konturek and co-workers (2) also found omeprazole effective against histamine-. pentagastrin- and urecholine-stimulated acid secre- tion when given as a continuous intravenous infu- sion to dogs. Half maximal inhibition was obtained at 0.4-1.1 pmol x kg-I x h-’.
inhibition of the stimulated acid secretion with The oral potencies of omeprazole and cimetidine maximal effect attained 1-2 hours after intra- were studied in the Heidenhain pouch dog. Both duodenal (i.d.1 (Figure 11, intravenous (Lv.) or compounds dose-dependently inhibited histamine- oral (p.0.) administration. stimulated acid secretion after oral administration.
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Table I. EDSO-values (mean and range) for Inhibition of Stimulated Gastric Acid Secretion in the Dog.
ED50 @nol/kg)
Animal Model Stim Route n Omeprazole Cimetidine
Gastric Fistula Pentagastrin i.d. 2 0.56 (0.43, 0.72) 3.87 (3.0, 5.0)a) Gastric Fistula Histamine i.d 4 0.26 (0.14-0.42) 1.83 (1.05-2.45) Gastric Fistula Histamine i.v. 4 0.35 (0.19-0.67) -
Heidenhain pouch Histamine p.0. 3 1.24 (0.68-2.3)b) 2.53 (2.3-2.7)
Effects were recorded during the second hour after administration. In each dog at least three different doses were tested. a) Effects during the first hour after administration. Corresponding values during the second hour were: 7.0 (6.8, 7.2)
b) Each dose was tested two or three times in each dog. pmol/kg.
n = number of dogs.
For omeprazole, the ED,,-values obtained after p.0. administration were 4-5 times higher than those ob- tained after i.d. or i.v. administration, whereas cimetidine was about equipotent after i.d. and p.0. administration (Table I).
Studies in the vagotomized acute fistula rat showed that omeprazole inhibited pentagastrin- (i.v., i.d. and p.0.) and carbachol- (id., Figure 2) stimulated acid secretion in a dose-dependent manner (1). Estimated ED,,-values were about 2.5 pmol/kg after i.v. and i.d. and 10-20 pmol/kg after oral ad-
Acid output wmol H+/h
0 i 2 3 h t Time i.d. adm.
Figure 2. Acute fistula rat. Effect of omeprazoIe (1.0, 0 ; 5.0, ., and 10.0, 0 pmollkg, cimetidine (20.0pmol/kg, A), and placebo (0, n=22) given intraduodenally at t = 0 on carbachol-stimulated (110 nmol x kg-' x h-l) acid secretion. MeanfSEM, n=5-10. * p <0.5; Mann- Whitney U-test. (From Larsson et al, (1)).
ministration. Cimetidine, a t 5 and 20 pmol/kg given i.d., inhibited pentagastrin-stimulated secre- tion in the rat by 56 & 10.0% and 76 5 5.4% (mean f SEM, n = lo), respectively. On carbachol- induced acid secretion, cimetidine at 20 pmol/kg produced approximately the same inhibitory effect as omeprazole at 1 pmol/kg (Figure 2).
The effect of omeprazole on basal acid secretion was compared with that of cimetidine in chronic fistula rats. The ED,,-value for omeprazole on basal secretion was estimated to be about 1 pmol/kg, whereas that for cimetidine was estimated to be about 25 pmol/kg (1).
In all these studies, the antisecretory potency of omeprazole was shown to be greater than that of cimetidine. In the dog, omeprazole was 2-7 times more potent, dependent on the route of administra- tion, and in the rat the difference was even greater, especially when tested o n basal or carbachol- induced acid secretion. In contrast to cimetidine, omeprazole was equally potent against different types of stimulation, indicating that the two com- pounds have different mechanisms of action.
The oral potency of omeprazole was lower than that found after i.v. or i.d. administration in both the dog and the rat. This is probably due to the instabil- ity of omeprazole a t low p H (1). In both species, omeprazole was administrated orally during basal (rat) or stimulated (dog) acid secretion, i.e., when there was a low p H in the stomach. Partial degrada- tion may therefore occur before absorption, resulting in a lower systemic bioavailability. An oral dose four times higher than the i.v. and i.d. doses
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was also required in the dog to produce a similar area under the plasma concentration curve (AUC).
Effects on pepsinogen secretion The effects of omeprazole on pepsinogen secretion in gastric fistula dogs have been studied by Konturek and co-workers (2). The output. was dose- dependently decreased owing mainly to the reduc- tion in the volume of gastric juice secretion. The results from in vitro studies have been contradic- tory. Firnmel and Blum (3) found a n increased pep- sinogen secretion from the isolated mouse stomach at high concentrations of orneprazole, while Fryklund et a1 (4) reported that omeprazole does not influence either basal or carbachol :stimulated pepsin release from isolated rabbit zymogen cells. Thein vifro effect of omeprazole therefore has to be further studied.
Duration of antisecretory effect after single-dose administration of omeprazole The duration of the antisecretory effect of single i.d. doses of omeprazole was studied on histamine- stimulated acid secretion in the dog (1). The doses used (0.5, 1.25, 2.5 and 5.0pmol/kg) were about 2, 5, 10 and 20 times the ED,,-value for peak inhibi- tion of acid secretion. In spite of the fact that orneprazole was no longer detectable in plasma, acid secretion was still inhibited 22-24 hours after administration (Table 11). Acid secretion was restored 48 hours after the two lower doses of orneprazole (Figure 3), whereas, after the two
Acid output mmnl H+/h
1 2 4 days Time
1.d. adm. Figure 3. Gastric fistula dog. Duration of antisecretory effect on histamine-stimulated secretion after single intraduodenal doses of omeprazole. 0 =Control (n=13-15), 0 =0.5pmol/kg, B=1.25pmol/kg, :-=2.5 pmol/kg, and A=S.O pmol/kg. Mean+SEM, n=3. (From Larsson et al, (I)) .
t
higher doses, control levels of acid secretion were not reached until the third or fourth day after ad- ministration (Figure 3). No difference was found in the duration of action between these two higher doses, indicating that maximal inhibition and dura- tion of action is already reached with 2.5 pmol/kg.
Table 11. Plasma levels and antisecretory effect!; (mean+SEM) after single-dose administration i.d. of omeprazole in the gastric fistula dog.
Omeprazole Plasma concentration Acid output-inhibition (/Lmol/k_p) (rmol/l) after 22-24 hours
~~~ ~ ~ _ _ _
30 min 24 h n vo n
0.5 0.54+0.13 <0.02 3 37*7 3 I .25 0.8, 1.18 <0.02 2 56+6 3 2.5 2.11+0.37 <0.02 3 81 +7 3 5.0 4.12k0.90 <0.02 3 92&2 3
11 number of animals.
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In the rat, the duration of the antisecretory effect of omeprazole was not as long as in the dog. The ef- fects of omeprazole, 5 and 20 pmol/kg, were measured at various times after i.v. administration to chronic gastric fistula rats (1). These doses of omeprazole initially (1-3 hours after administra- tion) gave 75 and 100 To inhibition of acid secre- tion, respectively. The inhibitory effect decreased linearily with time and the acid secretion rate reached the control level about 10 and 13 hours after the two doses, respectively.
Relation of the antisecretory ef- fect to plasma levels and elimina- tion of omeprazole in the dog Plasma levels of omeprazole were measured after i.d. and i.v. administration of 0.25 pmol/kg in the gastric fistula dog and after oral administration of 1 pmol/kg in the Heidenhain pouch dog (1). These doses correspond approximately to the ED,,-doses regarding inhibition of acid secretion. Omeprazole
Plasma concentration pnolil 1 .o
0.10
0.01
n 0 1 2
Time Figure 4. Plasma concentrations of [ ''C]-omeprazole given intravenously (0.24 pmol/kg, n = 2, 0 ) intra- duodenally (0.25 prnollkg, n = 3 , m) in the gastric fistula dog and orally (1 junol/kg, n=3, 0) in the Heidenhain pouch dog. MeanASEM. (From Larsson et aI.SW.
was rapidly absorbed, reaching peak plasma levels within 20 minutes and 1 hour after i.d. and oral ad- ministration, respectively (Figure 4). The elimina- tion half-life in plasma was - 1 hour, independent of route of administration. After correction for dosage differences the i.d. and oral bioavaitabitities were calculated to be -70 To and -15 '-70, respectively.
The elimination half-life in plasma of omeprazole is thus short compared with the long duration of in- hibitory action. Marked inhibition of acid secretion is maintained long after plasma levels of omeprazole have decreased below detection limits. However, autoradiographic studies in the mouse ( 5 ) have shown that omeprazole may accumulate in the gastric mucosa. Sixteen hours after an i.v. dose of labelled omeprazole radioactivity remained only in the gastric mucosa, and there predominantly over the tubulovesicular system and secretory mem- branes of the parietal cells. This observation in- dicates a rather firm binding of the inhibitory molecule to structures associated with acid forma- tion. However, in vitro studies have shown that, both in the guinea pig gastric mucosa (6) and in parietal cells (7), the inhibitory effect may be revers- ed by washing.
The finding that there was no correlation between the plasma concentration and the inhibitory effect gave rise to the question whether the effect of a sub- maximal dose of omeprazole was correlated to the peak plasma level or not. A defined dose of omeprazole was therefore infused i.v. over a period of either 22.5 minutes or 2 hours 38 minutes in dogs (8). The areas under the plasma concentration curves (AUC) were approximately the same in the two experiments, but the peak plasma levels dif- fered by a factor of five (Figure 5) . When measured 4-5 hours after the start of the experiment, acid secretion was inhibited by about 50 To in both ex- periments (Figure 5 ) , indicating that the AUC and not the peak plasma level determines the effect of omeprazole. In Figure 6, the inhibitory effects after various routes of administration of omeprazole in the dog have been plotted against the correspond- ding AUC:s. As can be seen, there is a good correla- tion between the effect and the AUC, with half maximal inhibition attained at approximately 0.5 pmol x h/l.
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Plasma concentration pmolil
0 1 2 3 4 5 h Time
Acid output % inhibition
100,
5 0
0 0 1 2 3 4 5 h
Time
Figure 5 . Gastric fistula dog. Relation between plasma concentration (left panel) and antisecretory effect (right panel) of omeprazole on histamine-stimulated acid secretion. The compound (0.18 pmol/kg) was infused i.v. either over 22.5 min ( 0 ) or over 2 h 38 min (A). Results are shown as the mean values from 2 dogs.
Acid output % inhibition
100
50
I I I 0.1 0.5 1 10 pnol x hi1
AUC Figure 6. Gastric fistula dog. Relation between area under the plasma concentration curve (AUC) and antisecretory ef- fect of omeprazole on histamine-stimulated acid secretion. The compound was given by various routes of administra- tion. The data after i.v.-infusion ( 0 ) were obtained by infusing different doses of omeprazole for either 22.5 rnin or 2 h 38 min. (cf fig 5 ) .
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Antisecretory effect of omeprazole during and after repeated administration in the dog As a consequence of the long duration of action of omeprazole, one would anticipate an accumulated inhibitory effect on acid secretion during the first days of repeated daily administration of a submaxi- ma1 dose. Some studies were therefore performed in in gastric fistula dogs to investigate this hypothesis. In addition, the relation between the inhibitory level during prolonged treatment (3 weeks - 1 year) and plasma levels of gastrin was studied.
Omeprazole, in a dose of 0.5 pmol x kg -l x day -1,
was given orally as enteric-coated granules (ECG) to gastric fistula dogs for three weeks (9, 10). The ef- fect on histamine-stimulated acid secretion was studied at intervals, either 3 or 24 hours after dose during that time (Figure 7). Three hours after the first dose acid secretion was inhibited by approxi- mately 20 To, whereas n o effect remained after 24 hours. A gradual increase in the inhibitory effect
Acid output % inhibition
was seen during the first five days of administra- tion, after which a steady state inhibitory level was reached, which was maintained during the rest of the treatment period. At steady state the inhibition was about 60 Vo the 3rd hour after administration and 35-40 070 during the 24th hour. Acid secretion tests, performed one week after the end of treat- ment, showed that acid secretion at that time was back to control levels. No effect was seen either on basal or o n food-stimulated plasma gastrin levels during the treatment.
In a similar study, omeprazole (2 pmol x kg-’ x day-’ given as a suspension in 0.5 To Methocel) was administered orally to dogs for two months (9, 10). During steady state the mean maximal and minimal inhibition of histamine-stimulated acid secretion recorded 3 and 24 hours after dosing was 82 and 35 To, respectively. After the administration period acid secretion reached control values within 4 days. No sign of a rebound effect was observed within the four weeks following the last dose. In this study n o effect was seen on basal plasma gastrin levels, but food-stimulated gastrin levels, recorded at the end of the treatment period, were slightly increased.
Number of doses of omeprazole
Figure 7. Gastric fistula dog. Development of the antisecretory effect of omeprazole during 3 weeks’ daily oral ad- ministration (0.5 pmol/kg given as ECG) on histamine-stimulated (400-500 nmol x kg-’) x h-’) acid secretion. Secretory tests were performed either 1-3 hours or 22-24 hours after dosing. MeankSEM, n = 4.
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In another study, gastric fistula dogs were treated with a supramaximal dose of omeprazole, 80 pmol x kg-' x day-', orally for one year (Sundell et al, to be published). During the treatment period, there was a nearly complete inhibition of histamine- stimulated acid secretion. Food-stimulated plasma gastrin levels were found to be increased approxi- mately 10-fold when determined after 3, 6, 9 and 12 months of treatment. This increase in plasma gastrin levels is probably secondary to the pro- nounced inhibition of acid secretion, since a low pH in the antrum normally inhibits gastrin release. After the end of the treatment the antisecretory ef- fect gradually decreased, and the plasma gastrin values had returned to control levels within 8 days.
These studies indicate that increased blood levels of gastrin might result on prolonged treatment with omeprazole at doses which nearly completely in- hibit acid secretion over 24 hours. The hyperplasia of the fundic mucosa which has been observed in dogs after one year of treatment with high oral doses may thus be a result of the trophic action of gastrin ( I 1) .
'Thus, there is an increasing inhibitory effect during r he first days of repeated administration, which is in accordance with the long duration of action. Dur- ing once-daily dosing a steady-state effect is reached after approximately five doses in the dog. The duration of action is unaffected by the length of the treatment period.
Protective effects against experimentally induced -
gastric mucosal lesions in the rat The effects of omeprazole against gastric mucosal lesions produced by necrotizing agents has been studied in the rat (12). Rats treated orally with omeprazole dose-dependently prevented gastric le- sions induced by 1 ml of absolute ethanol, 200 tng/kg aspirin in 0.15 M HC1, hypertonic NaCl (35 %I) or 0.6 M HC1. The calculated ED,,-values for omeprazole protection were 40, 12, 38 and 10 pnol /kg, respectively. The maximal protective ef- fect was obtained when omeprazole was given 15-60 minutes before ethanol. The oral ED,, of
Gastric lesions crn
I
omeprazole for inhibiton of acid secretion was estimated to be about 10 pmol/kg in parallel ex- periments. The protective effect is thus obtained in or above thedose rangeof acid secretion inhibition. However, the protection seems not to be due to reduced acid secretion, since omeprazole did not protect against ethanol-induced lesions when given i.v., in doses (20 and 40pmol/kg), which completely inhibit acid secretion. In addition, the duration of the protective effect after oral administration of 80 pmol/kg was about 3 hours, (Figure 8), whereas acid secretion remains completely inhibited for at least 10 hours following the same dose. Similar results have also been reported by Kollberg et a1 (13) and Konturek et a1 (14).
The lesions produced by ethanol were found to be associated with an increased vascular permeability, as demonstrated following i.v. injection of lZ5I-
albumin (1.75 pCi/rat) (15). Oral administration of ethanol induced leakage of the radio-labelled albumin into the gastric juice and corpus wall. Omeprazole, given orally, dose-dependently re- duced the leakage of albumin and this effect was correlated to a reduction of the macroscopical le- sions (Table 111). Cimetidine neither affected the visible lesions, nor the albumin leakage induced by absolute ethanol.
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Table 111. Effects of omeprazole and cimetidine on gastric mucosal lesions and vascular permeability (leakage of ‘251-alburnin given i.v.) induced by absolute ethanol.
(n=7-19) Radioactivity, cpm/g wet weight
Gastric lesions, cm
Control (no ethanol) 0 Vehicle 11.2f0.6 Omeprazole, 40 pmollkg 5.4f1.2 Omeprazole, 80 pmol/kg 1.0f0.3 Omeprazole, 160 pmol/kg 0.6k0.2 Cimetidine, 80 pmol/kg 11.6k0.6 Cimetidine, 320 pmol/kg 12.0+0.8
Gastric juice
5741+ 809 16627k1758 7998k-1704 6507f 764 5362f 910
16428 f 2434 20693k-2392
Corpus wall
3292f 431 9030f 735 6089k 1591 4392k 313 3617f 101
11 170f 1837 14462t2467
The mechanism of gastric mucosal protection by omeprazole is unknown. Prostaglandins are known to protect against experimentally induced lesions. It has also been suggested that the protection provid- ed by “mild” irritants like 20 Vo ethanol or weak alkali and acid is due to increased formation of pro- tective prostaglandins (16). To investigate the pos- sible involvement of endogenous prostaglandins in the protective effect of omeprazole, rats were pretreated with indomethacin, to inhibit pro- staglandin synthesis, before administration of omeprazole. The ED,,-value for omeprazole pro- tection in these animals was about 48 pmol/kg, which is slightly higher but not significantly dif- ferent from the the ED,, (40pmol/kg) obtained in control animals (12). The protective potency of omeprazole is thus very little affected by in- domethacin pretreatment, indicating that inter- ference with the synthesis of endogenous pros- taglandins is of little importance for the protective effect of omeprazole.
One possibility could be that the protective effect is due to an increased secretion of bicarbonate from the gastric epithelial cells. However, omeprazole, in concentrations - mol/l) which complete- ly inhibit acid secretion in the isolated guinea pig fundic mucosa (6), had no effect on either basal or on carbachol-stimulated alkaline secretion in the guinea-pig antral mucosa (17). This is in agreement with the finding of Konturek and co-workers (2), who reported that omeprazole was devoid of effect on both gastric and duodenal alkaline secretion in the conscious dog.
General pharmacology The specificity studies with omeprazole have so far revealed no other important pharmacodynamic ef- fects than those attributable to inhibition of gastric acid secretion on one hand and protection against experimentally induced gastric lesions on the other.
Thus, omeprazole is devoid of histamine H,- receptor blocking properties, as was shown in the isolated guinea pig right atrium (6). Omeprazole
and 10-4mol/l) neither influenced the basal rate nor the histamine-induced increase in the beating frequency, and no shift in the concentra- tion-response curve to histamine was seen. Cimetidine and 10-5mol/l), on the other hand, caused a parallel displacement to the right of the histamine concentration effect curve, an effect in agreement with its histamine H,-receptor-blocking properties.
The effect of omeprazole on gastric emptying has been studied in intact rats by the method of Droppleman et a1 (18). Omeprazole or vehicle was given p.0. (40-400 pmol/kg) or i.v. (5-80 pmol/kg) in a single dose one hour before a test meal. Ninety minutes after administration of the test meal 50-65 070 or about 35 Vo of the stomach contents had been emptied in control p.0. or i.v. experiments, respectively. Atropine at 1 mg/kg (p.0.) was a potent inhibitor of gastric emptying. Only at a very high oral dose (400 ,umol/kg) did omeprazole affect gastric emptying, whereas a t lower oral doses and after the i.v. doses no effect was seen (Figure 9) (Larsson, unpublished). Omeprazole thus inhibited
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of test meal emptied
Dose omeprazole
Figure 9 Gastric emptying of a test meal given to con- ~c ious rats. Omeprazole was given (I.v., or p.0. 0 ) 1 h before the test meal. The percentage of the total test meal emptied YO min after the meal is given as meankSEM, 11 = 4- 10
gastric emptying in intact rats a t a ‘dose (400 pmol/kg) about 40 times the oral ED,,-value for in- hibition of gastric acid secretion. However, when given i.v. at 80pmol/kg, no effect on the emptying rate was seen. This i.v. dose produced a plasma level of omeprazole similar to that found after 400 pmol/kg, P.o., suggesting that the effect is topical and not arising from circulating compound. Fur- thermore, i t is not secondary to inhibition of acid secretion, since total inhibition results ,From both doses. After seven days’ oral treatment with umeprazole at 400 pmol/kg no attenuation of the inhibitory effect on gastric emptying was seen.
Omeprazole, in doses up to 20 times the ED,,-value for antisecretory effect in the rat, had no effect on intestinal transport. The distance which a suspen- sion of charcoal (0.15 g/ml, p.0.) was transported, was the same in control rats as in rats pretreated (1 hour before charcoal) orally with omeprazole (20, 40 and 200 pmol/kg) (Larsson, unpublished).
The effect of omeprazole on pancreatic secretion has been studied by Konturek and co-workers (2) in gastric and pancreatic fistula dogs. They found that omeprazole 1 p o l / k g given i.d. did not affect the pancreatic secretion of bicarbonate and protein in- duced by i.v. secretin (2 U/kg x h) or intraduodenal instillation of HCl(8 mmol/h). However, the same dose of omeprazole reduced meal-stimulated pan- creatic bicarbonate secretion. This effect is prob- ably due to diminished duodenal acidification following the inhibited gastric acid secretion. Sundell and Preshaw (19) also found that omeprazole, 0.5 and 10 ,umol/kg i.v., was devoid of effects on secretin-stimulated pancreatic secretion of bicarbonate in dogs provided with gastric and pancreatic fistulas.
The basal and mean arterial blood pressures were unaffected by omeprazole in doses of 8,40 and 200 pmol/kg, administered i.d. in the anaesthetised dog. Neither were the changes in blood pressure nor in heart rate induced by vagal stimulation, carotic occlusion, acetylcholine, noradrenaline, isoprena- line or histamine affected in the same preparation (Table IV) (Sjoquist, unpublished).
Table IV. Effect on mean arterial blood pressure and heart rate in five dogs submitted to various test procedures before and after administration of omeprazole in increasing doses (8, 40 and 200 pmol/kg). (MeankSEM, n = 5).
. ..
Response (mean valueskSEM) Before omeprazole after omeprazole in cumulative doses Significance
Vagal stim .4cetylcholine lsoprenaline Noradrenaline Histamine Carotic occl.
Vagal stim lsoprenaline
- 1 O . O k 3.2 -57.0k11.2 -65.0k 6.9 +64.0k 6.2 - 5 O . O k 6.5 +84.0+ 5.6
-22.8k 4.3 +88.2-t 6.2
8 pnol /kg 40 pmol/kg 200 pmol/kg
MEAN ARTERIAL BLOOD PRESSURE (mm Hg) -16.Ok 3.3’’ -13.0-t 3.4 -17.0-t 3.4 -51.0212.4 -53.0k11.2 -47.0210.8 n.s. -66.0f 6.6 -60 .02 4.5 -56.0k4.8 n.s +63.0+ 8.6 +65.0+ 9.4 +59.6+10.4 n.s -51.0+ 6.2 -47 .0k 6.2 -46.0k5.1 n.s. +83 .0k 9.4 +88.0+ 9.4 +81.0+11.3 n.s.
HEART RATE (beats/min) -18.4k 3.3 -23.4k 4.0 25 .62 4.6 n.s + 8 7 . 4 2 6.9 +87 .82 6.1 86.0k 8.6 n s .
~~
1 ) Statistical significant (p c0.05) difference from control value, assessed by Student’s t-test.
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Omeprazole was also devoid of effect o n kidney ex- cretion of hydrogen ions (Ek and Bjorkman, un- published). This was shown in anaesthetised dogs with systemic acidosis experimentally induced by i.v. infusion of 0.25 M HCl (1.5-0.75 ml/min).
Figure 10 shows that omeprazole (IOpmoVkg, i.d.) affected neither the pH of blood nor that of urine. On the other hand, acetazolamide, a carbonic anhydrase inhibitor, caused an increase in urine p H and a lowered blood pH, indicating an inhibition of
Blood PH
7.4
7.2
7.0
6.8
0 1 2 3 4 5 6 h Time
Urine PH
0 i 2 3 4 5 h Time
Figure 10. Experimentally induced acidosis in the anaesthetized dog. Effects of omeprazole (10 fimol/kg, i.d., 0 ), acetazolamide (15 mg/kg (priming dose) followed by 5 mg/kg, h, given i.v., A) and vehicle (0.5 Yo Methocel, i.d., 0) on blood pH (upper panel) and urine pH (lower panel). Results are given as mean of 2-3 experiments.
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renal excretion of acid. The experiments suggest that even a supramaximal dose of omeprazole does not affect the renal carbonic anhydrase 01- any other enzyme handling the excretion of protons in the kidney.
Taken together, the overall impact of the present ex- periments is that omeprazole seems to be very selec- tive in its gastric acid antisecretory and gastric pro- tective actions. It is a very potent antisecretory agent in the dog and rat. It is active against different stimuli and after various routes of administration. Its very long duration of action is unique. As a con- sequence of the long duration of action, repeated administration of submaximal doses will result in a cumulative antisecretory effect during the first days of administration until a steady-state level is reach- ed. Interestingly, omeprazole also seems to have a protective effect in the rat stomach against ex- perimentally induced lesions. The mechanism of this effect is not known a t present, but seems to be a result of a local effect on the gastric rnucosa. In clinical studies, omeprazole will be given as enteric- coated granules and will therefore not be exposed to the gastric mucosa. Thus, it is doubtful whether or not this property of omeprazole is of any clinical significance.
References Larsson H, Carlsson E, Junggren U , et a]. Inhibition of gastric acid secretion by omeprazole in the dog and rat. Gastroenterology 1983;85:900-7.
Konturek SJ, Cieszkowski M, Kwiecien N, Tasler J , Bilski J. Effects of omeprazole, a substituted benz- imidazole, on gastrointestinal secretions, serum gastrin, and gastric mucosal blood flow in dogs. Gastroenterology 1984;86:7 1-7.
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Fryklund J, Wallmark B, Larsson H, Helander H. Effect of omeprazole on gastric secretion in H+,K+- ATPase and in pepsinogen-rich cell fractions from rabbit gastric mucosa. Biochem Pharmacol 1984; 331273-80.
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Helander HF, Ramsay C-H, Regirdh C-G. Locali- zation of omeprazole and metabolites in the mouse. Scand J Gastroenterol 1985;2O(suppl 108):95-105.
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15. Mattsson H, Anderson 1<, Carlsson E. OmeprazoIe protects against vascular protein leakage in the rat stomach exposed to ethanol. Fed Proc 1984;43:945.
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17. Mattsson H, Carlsson K, Carlsson E. Omeprazole is 19. Sundell GW, Preshaw RM. Effect of omeprazole on devoid of effect on alkaline secretion in isolated gastric and pancreatic secretion in the dog. Proc 9th guinea-pig antral mucosa. In: Allen A, Flemstrom Internat Congress Pharmacol, London 1984. G, Garner A, Silen W, Turnberg LA, eds. Abstract No 264P. Mechanisms of mucosal protection in upper gastrointestinal tract. Raven Press 1984, 141-6.
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