Orug Disposition
Cion. I'tIarmarol"MI 20 (I): 18-49. 1991 OlI2· ~96J!9 I /OOO I .()(l38/S06.00/O
C Ad"ln!rmahOnal llmllro All nlhls l"C'SCT'Ved. cPl
Clinical Pharmacology of Omeprazol. Colin W. Howden Unlv~rsll y Departmenl of Medicine and Therapt'ul1cs. WC'Slrm Infirmary. Gl1S10W Gil 6NT. Scotland
Cont~ntJ
SummaI)' .......................••....•...•......••.....•.....••••....•.....•••.......•... I. Chcml51ry and Pharmaoolos,y of OmeprlIlolr
1.1 Ow-mlSlry ...................... 1 2 Mrxk of A1'" lIl)n 2. Pharmacodynamics m Humans ........................... .,..... . 2.1 Effect on Basal ACid Ou t put. .................... ............................................ .
2. 2 Effect on Peniapsmn-Slimuilled Acid Output ......................................... .. 2. 1 Effect on Insuiln·St,mlllatro ACid Olltput ..................................................... .
.. 39 J9
.... 39 ... 39 J9
.......... 39 ............ 40
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. ......... 41 2.4 Effect on 24-HOllr Intnp$tnc: At ldll y .. 41 ............................ . ....... 42 2.6 Effect on I'cpsm Secretion ..................... . 2.7 Effect on Intrapstrie Bacteria and Bacterial Prodllcts .... 42 ...................................... 42 2.8 Effects on EndOCrine Flinction ............................... 2.9 Effects on Renal TlIblilar Flinctlon .............................................................................. 42 ..... 42 3. Pharmacokinetics In Hlimans .......................... . ........ 42 3.1 Absorption and ~TUm Cont"('ntntions 3.2 Distriblition ........................ 3.3 Metabolism and Elimination ........... . . 43 3.4 InnllCnce of Disease Stales o n tile Pharmacokinetics or Om~pn~olc .......... .... 44 4. Drua Interactions ........................................................................... _...................................... 45 4. 1 Diazepam ................................................................ ................... 4S 4.2 AmlnopllrnazollC (Aminopynnr) and PllrnazollC (AnllpYrlne) .................................. 45 .. 45 4.3 Pllrnytoin . 4.4 Propnnolol ...... 45 4.5 warfarin .. 45 4.6 Amo~ yclilin and Ibcampicillin ......... .. 4S 4.7 Nlrc(!lplllC ........................................... ...... 45 4.8 Anlllrnb and Mrtoclo pnmldr ......... ...... 46 l Tllcrapclltic Uses of Omepn~olc .......... ................................ 46 5. 1 Dliodenal Ulcer ................................ 5.2 Gastric Ulcer ............................................... ..................................... 46 5.3 PePIiC Ulcerallon Refracl(lI"y to Treatmrnt .............................................. .... 47 S.4 Rrflll~ OcsoplllllliS ............................................................. ........................ ..... 47 5.5 Zollinger-Ellison Syndrome ........................................................................ ...... 47
2.5 Effect on Pluma Gasmn Levels
"
.,
Clinical
Pharmacolog~
of Omeprazo!t·
Su mm(u J'
J9
Omcprazo!c IS a spc(iflc inhibitor of H-. K '-ATPase or 'prmoll pum p' In parlctal cclls. This cnz) me IS responsibk for the final step In the process of ac .d SCCTetlOn: ome prazoic blocks aCid !.Ccr('tlon In responsc to all stimuli. Single doses produce dosc-depen den t inhibition with mereasmg elTcrt O\er the first fcv. days. reachmg a ma\lmum after about 5 da) s. Doscs of omeprazole 20mg dall~ or greater arc able 10 qrtually abohsh mtragastnc aeldl[~ In most mdl\lduals. although lov.cr do!.Cs ha'c a much more vanable effect Omepra10le causcs a dosc-depcndcnt Incrcasc In gastrin le\'els. OmepraLOk mUSl be protected from Intra gastric aeld v. hen ginn oral I). and IS the refor;.' admmlstcred as encapsulated entenc-coatcd granules. :\bsorpllon can be crratlc but IS gcnerall~ rapid. and Illluall~ the drug IS \lldel) dlstnbutcd. IllS high!) pro tcm-bound and cxtcnSl\cl) metabolised. Its elimmatlon half-life IS about lh but Its pharmacotoglcal elTl'Ct la~ts much longer. smCl' !lIS prcfcrcnllaH~ concentrated m panetal cells v.here 1\ forms a co' aiI'm lin kage v. IIh H'. K' -ATPase. \lhlch 11 Irre'crSlbl) mhlbllS. Omeprazole binds to hepatiC cytochrome P450 and mhlblts o.\ ldaIlH metabolism of some drugs. the mosl important helllg phe n)lOlll. Omcprazote has produced short te fm healing rates superior to the hlstammc ti ~· reccptor antagolllsts 10 duodenal ulcer. gastric ulcer and rcnu ~ ocso phag1\ls. It has also been shov.·n t o be hlgh l) elTectlve III heali ng ulcers v.hlch ha,-c failed to respond 10 ti 1receplOr antagonists. and has l)l"Cn e., tremcl) \'aluable In treallng pallenlS v. IIh ZolllngcrEtlison s)ndromc.
I. C hemistlJ' and Pharmacology of Omepra;-.ole 1.1 Chemistr)
The molecular structure of omcprazok is composed of a substituted p)ridine ring li nked 10 a benzimidazole by a sulfoxide chain (fig. I). It s molecular weight is 345 daltons. Omeprazok is a lipophilic weak base, and will thcrefore prcferentiall} accumulatc in an acidic environment such as the secretory me mbrane of the parietal cell. 1.2 Mode of Action
Omeprazole is avidly taken up by thc parietal cell. In an addic pH it becomcs converted to its activc form, a sulphenamlde. b) protonation. In
this form, the drug produces an irreversible linkage via a disulfide bond with the e nzyme H'. K'AT Pa~ or 'proton pump' (fig. 2) which is rcsponsible for the active ~cre t ion o f h ydrogen i o ns by the parietal cells (Sachs & wall mark 1989: Wallmark 1989) . This action makes omcprazok unique a mong cxisting gastric an tlsccretory drugs which arc competith'e antagonists at specific cellular receplOrs on the basolateral aspect of the parieta l cell. Th rough its irreversible inhi bition of H+. K·- ATPase. orneprazok blocks gastric acid secretion in response to all known stim uli incl uding a~en t s such a sdi bu tryl cyclic adenosine monophosphate (d\)
], Pharmacod),namics i ll Humans 2.1 Effect on Basal Acid Output
Fig. 1. Chcmlcal structure of omrpralO!c
Following oral admi nistration of o meprazole in ils enca psu lated enteric
Clln. l'hurmU('QIi.III(,I. 10 (I ) NYO
40
similar group of6 subjects given omeprazolc 60mg dail y, inhibition of basal acid output was 91.7% after the first dose and 99. [% after the seventh. In a separate study, the effects of7 da ys' administration of omeprazole IOmg dail y were assessed (Howden et a1. 1985a). A single dose of IOmg did nOI significantly affect basal acid output. but after 7 da ys of dosing mean basal acid output was reo duced by 93%. However. there was a high degree ofinterindividual variabili ty in response to this low dose. These studies show a dose-dependent effect of omeprazole on inhibition of basal acid outpu t. They also show variability in response to low dose orne· prazole, and increased anti secretory effect with repeated dosing.
o
2.2 Effect on Pentagastrin-Stimulated Acid Output Active intllbitor
o
Enzyme-SH
Enzyme-inhib4tor
comple~
Fig. 2. Diagram of lilt InlNl'Iclion of lh~ aC1lv31Cd form o f o mc pr.lzolc wilh gastTiC H ·. K'-A TPasc:.
achieved aftcr about 6 hours: in a group of6 healthy male subjects given omeprazole 30mg, basal acid output measured 6 hours later was reduced by 66% (Howden et a1. 1984a). After I week of daily administration of the same dose, the inhibition of basal acid output had risen to almost 100%. In a
Intravenous infusion of pentagastrin 1.2 ~g/kg for I hour increased gastric acid secretion in a group of 6 healthy male subjects fro m a mean ( ± SO) basal value o f 4.3± 3.4 mmol/ h to a plateau value of 35.4 ± 5.4 mmol/ h (Howden et al. 1984a). Omeprazole 30mg reduced the pentagastrin-stimulated plateau acid outpu t t o 0.2 1 ± 10.1 mmol/ h (-71.2%~ P < 0.05). After 7 da ys of dosing with omeprazole 30mg daily, this was further reduced to 0.6 ± 1.0 mmol/ h (-98 .4%~ p < 0.01). In subjects given omeprazole 60mg daily. pretreatment plateau acid output was 37.1 ± 10.6 mmol/ h. After I dose this was reduced to L7 ± 2.3 mmol/ h (-95.3%; p < 0.01); after the seventh dose, it was 0.4 ± 0.2 mmol/ h (-99%; p < 0.01). In subjects given omeprazole 10mg dail y (Howden et al. 1985a). pretreatment plateau acid output was 23.3 ± 8.2 mmol/h. Six hours after a single dose of 10mg, the figure was 23. 1 ± 8.6 mmol/h (not significant) but at a sim ilar time after the seventh daily dose it was 7.8 ± 6.7 mmol/ h (-66.5%; p < 0.0 1). Again. there was a high degree ofi nterindividual variability in response to the low dose. In a group of patients with healed duodenal ulcer, pentagastrin-stimulated acid output after 7 da ys of dosing with placeoo or omeprazole 5 or
41
('lIn1(al Pharmacology of Omcpra:wlc
10mg daily was measured 14 hours after the final dose (Howden et aL 1986a), Toml out put was 42.9 ± 4.9 mmol fo llowing placebo. and 34.5 ± 9.8 and 32.3 ± 8.7 followi ng omeprazole 5 and IOmg, respectivel), Neither of the reductions in output produced by these low doses of omeprazole was significanl. 2.3 Effect on Insulin-Stimulated Acid Output Omeprazole 30mg as a single oral dose reduced the stimulated acid output induced by an inlTavenous infusion of insulin 0.03 U! kglh (Utley et a1. 1985) from 16.8 ± 2.2 to 4.3 ± 1.8 mmol!h (-74%: p < 0,05). A sim ilar group of subjects received a single dose of omeprazole 60mg. and in this group the insulin-stimulated acid output was reduced from 12.3 ± 2.6 to 3.4 ± 2.1 mmol! h (-73%: p < 0.05). 2.4 Effect on 24- Hour Intragastnc Acidity In a group of9 patients with duodenal ulcer in clinical remission. a regimen of omeprazole 30mg dall) for I week nrtually el iminated intragastric acidit). with mean hourly hydrogen ion activity falling from 38.5 to 1.95 mmol/ L (Walt et a1. 1983). The median tntragastric pH rose from 1.4 to 5.3. representing a much greater increase than that achieved b) conventional doses of existing histamine H1-receptor antagonists. In another s t ud~. 12 duodenal ulcer patients re· cei\ed omeprazole 20mg daily for 28 days (Lan· zon-Miller et a1. 1987). AI the end of that lime. median tntegrated 24-hour tntragastric aCidity had fallen from 1148 to 36 mmol/ L ' h (-97%), T he same pallen ts also receiv("d a separa te course of \T("alment .... ith ranitidin(" 150mg twice daily: Ihe m("dlan tn tegrated 24-hour tntragastric acidity with that treatm("nt was 490 mmol! L ' h (-57% compared wllh pretreatment values). Omcprazole 20mg dai ly for 8 days reduced intragastric acid It) by around 99% in 6 patients wi th healed duodenal ulcer (Naesdal et a1. 1987) but had a much smaller effect on another 4 patients in the
same study. indicating some degree of interi ndividual vanabili ly in response to th is dose. Finally, a dosage regimen of omeprazole 5 o r 10mg daily for 7 days did nOt have any significan t effect on 24-hour intragastric acid ity in a gro up o f 6 patIen ts with healed duodenal ulcer (Howden et at. 1986a). 1.5 Effect on Plasma Gastrin Levels Plasma conce ntrations of a wide variety of gastro intestinal pcptides were measured in 6 healthy subjects 6 hours after a single oral dose of omeprazo1c 40mg (Allen et al. 1984). The basal level of gastrin was significan tly (p < 0.05) increased fro m 13 ± 6.8 to 28.2 ± 8.3 pmol/ L T he integrated gastri n response to a meal was also increased. but failed to reach statistical significance. No significa nt changes were found in the concenlTations of any of the olher peptides measured. In a group of 12 healt hy volunteers given omeprazole 4001g daily fo r 9 days by Festen et a l. (1986). fast ing serum gastrin levels increased from 36 ± 3 to 49 ± 6 nglL (p < 0.0 1) after the firs t dose and to 59 ± 6 nglL after the nint h (p < 0.002). A nonsignificant increase in serum gastrin levels was found in I study of 10 duodenal ulcer patients given omeprazo1c 20mg daily for 8 days (Naesdal et a1. 1987). Omeprazole 5 or 10mg dai ly for 7 days also produced no alteration in fasti ng gastrin levels in a group of6 duodenal ulcer patients (Howden et al. I986a). However. the median integrated gastrin response to a meal was significantl) increased from 29.210 67.0 pmol/ L· h (p < 0.05) follo wing 7 days of omeprazoJc 10mg daily. The median integrated 24-hour plasma gastrin was SIgni fi cantly raIsed from 328 to 1519 pmoII L · h In a group of 12 duodenal ulcer patients given omeprazo1e 20mg daily for 28 days (Lanzon-Miller et al. 1987). The median integrated 2-hour plasma gastrin fo r the same group of pa tients given ranitidine I 50mg twice daily for 28 days was 799 pmoll L · h. Omeprazole produces a dose-dependent increase in gastrin levels. The rise in integrated 24hour gastrin is directly proportional to the reduc-
C/III. Pharmacolim('f. } O(I) 1990
42
tion in integrated 24-hour intragastric acidity (Lan. zon-Miller & Pounder, personal communication). 2.6 Effect on Pepsin Secretion Although omeprazole has a dramatic effect on secretion of gastric acid, it does not significantly affect that of pepsin. Such a finding is consistent with the specifi c action of the drug on parietal cells without an effect on the function of the pepsi nsecreting chief cells. Thompson ct al. ( 1985) found no significant alteration in pepsin output after 4 weeks of omeprazoIc 20 or 40mg daily in 9 patients with duodenal ulcer disease. Omeprazo]e IOms daily for 7 days did not affect basal or pentagastrin-stimulated pepsin in 6 healthy volunteers (Howden et al. 1985a), and a higher dosage of 30 or 60mg daily for 7 days did not affect basal pepsin secretion in heallhy volunteers (Howden et a\. 1984a). Similarly, 12 healthy subjects given omeprazole 40mg daily for 9 days did not display any alteration in pentagastrin-stimulated pepsin o ut put (Festen et al. 1986). 2.7 Effect on Intragastric Bacteria a nd Bacterial Products Ten healthy male subjects were given omeprazole 30mg daily for 2 weeks in the study of Sharma et a\. (1984). Gastric ju ice sampled 22 hours after the final dose of omeprazoie showed a significant (p < 0.01) rise in the concentrations of bacteria, nitrite a nd N-nitrosam ines and a nonsignificant reduction in nitrate levels. The profound inhibition of gastric acidity had allowed proliferation of intragastric bacteria wit h consequent red uction of dietary nitrate to ni trite and the production of Nnitrosamines. All these changes had resolved within 3 days of stopping omeprazole. 2.8 Effects on Endocrine Function The effects of high dose endocrine function have been st udied in healthy male subjects (Howden et al. 1986b; MacGilchrist et al. 1987). Omeprazole 60mg daily for 8 days had no effect on t he basal
levels of thyroid-stimulating hormone (TSH). follicle-stimulating hormone (FSH). luteinising hormone (LH), prolactin (PRL), thyroxine (T 4), triiodothyronine (T), conisol or tes tosterone. In addition, the respo nses ofTSH and PRL to stimulation with th yrotrophin-releasing hormone and the responses of FSH and LH to stimulation with lutcinising hormone-releasing hormone were unaffected by omeprazole. An in itial finding ofa reduc tion in the peak cortisollevel in response to stimulation with synthetic corticotrophin (ACTH) in a g ro up of healthy male subjects receiving omeprazole 60mgdaily for 8 days (Howden et al. 1986c) was not subsequently confirmed (MacGilchrist et al. 1987). However, in vi/fO studies using isolated bovine adrenocortical celts showed that incubation wi th omeprazole produces a marked dose-dependent inhibition of stimulated cortisol release (Howden et al. I986c). This is unlikely to have any sign ificance for the use of orne· prazole in humans, since extremely high concen· trations of omeprazole were necessary to produce the effect. 2.9 Effects on Renal Tubular Function Omeprazole 60mg administered daily for 7 days did not affect 2~hou r urinary electrolyte excretion or urinary acidification in response to oral am· monium chloride in a g ro up of8 healthy male subjects ( Howden & Reid 1984).
3. Pharmacokinetics in Humans 3.1 Absorption and Serum Concent rations Since omeprazole is acid·labile, it must be protected from the action of acidic gastric juice when given by mouth. In some studies, this was achieved by administering the drug with oral sodi um bi· carbonate (e.g. Cederberg et al. 1989). Absorption of omeprazole was rapid, with peak plasma concentrations being reached within O.5h. This d rug is usually administered as encapsu· lated enteric-(oated granules. The release from this formulation and subseq uen t absorption are erratic and do not follow classic pharmacokinetic prinei-
Chnlcal Pharmacology of Omeprazole
pies. Studies have shown marked interindividual vanability in both the rate and exten t of absorption, In most healthy male subjects given omeprazolc 10. 30 or 60mg daily (Howden et a1. 1984b. I 985a). peak plasma omeprazole concentrations were achieved by 1.5 hours. although there was marked variation in individual peak concentrations. The ranges were 58 to 154,22310 1160 and 860 10 ]8]0 .ugfL after single doses of 10. 30 and 60mg. re· spectively. The area under the plasma omeprazo[el time curve from administration until 8 hours after the dose (AUCW_SI) calculated by the li near trap. ezoidal rule also showed marked interindividual variation: the ranges after single oral doses of 10. ]0 and 60mg were 156 10 428. ]]8 to 2270 and 1380 to 5000 .ugfL· h. respectively. Arter 7 days of treatment with these doses ad. ministered daily. the AVCW_8) had increased from that of the first dose (Howden et a1. 1984b. 1985a): the mean increases were 45% after 10mg daily. 86% after ]Omg daily and 128% after 60mg dai ly. This implies a degree of nonlinearity which has alro ocen noted by others. In a group of healthy volunteers given omeprazole either 10. 20 or 40mg daily for 5 days. the increases in AUC from days I to 5 averaged 21. 69 and 182%. respectively (Andersson et a1. 1989). The most likely explanation fo r the observed rise in AUC is that omeprazole absorption increases With repeated dosmg due 10 a progressive suppression of acid secretion. Less omeprazole is degraded once acid secretion is inhibited. leaving more available for absorption. The increase in AUC cannot be explained b) decreased elimination. since the clearance of omeprazole docs not change with continuous treatment (Ching et al. 1990). The true bioa vailability of omeprazolc has been estimated at 35% after a single dose. increasing to approximately 60% following repeated daily doses (Cederberg et al. 1989). The time of ad ministration docs not matenally influence its absorption. In 8 healthy male subjects given omeprazole 40mg daily for 5 days. the parameters of time to peak concentrallon. peak concentration and AVC were similar
4J
whether the doses had been taken at 0900 or 2100h each day (Prichard et a1. 1985). ].2 Distribution Omcprazole is. initially. rapidly distributed to extravascular sites. The mean volume of distribution in 8 healthy volunteers given 20mg ora lly was reported by Regardh et a1. ( 1985) to be 0.31 L/ kg. with a range of 0.19 to 0.45 L/ kg. This would be compatible with localisation of the major fraction of omeprazolc within extracell ular water. Penetration of the drug into red blood cells is low. the ratio between whole blood concen trations and those in plasma being in the region of 0.6. Omeprazole is more than 95% bound to plasma proteins in humans. principally albumin and itt-acid glycoprotein (RegArdh el al. 1985). [t subsequently becomes preferentially concent raled within parietal cells. ].] Metabolism and Elimination Omepra70le is almost entirely cleared by metabolism. so that vinually no unchanged drug is excret('(! (Clissold & Campol i-R ichards 1986), After oral or In travenous administration of [14C]_ome_ prazok. more than 80% of the radioactivity was recovered in the urine. with most of the remainder in the faeces. No unchanged drug was found in either urine or faeces (Cederberg el al. 1989: Regardh 1986). The main metabolites in humans are the sulfone and hydroxy-omeprazole (fig. ]). The sulfone metabolite docs not possess any antisecretor) activity. whilc hydroxy-omeprazole is only weakly antisecretory (Cederberg et al. 1989). Arter low dose omeprazole labelled with t4c was given intravenously to volunteers. 16% was recovered in the bile within the first 4 hours (Lind et al. [987). Negligible amounts of drug were recovered from gastric juice over this time. indicating that bi liary excretion is the only imponant gastrointestinal route of elimination. Elimination half·life after oral omeprazole has been estimated al about 1h (Cederberg et al. 1989: RegArdh ct a1. 1985). Omeprazole is almost entirely cleared from plasma at 4 hours after oral admin-
Om. Pharmarolwll't 10 (I) 1990
44
Omeprnole .c:id -COOH _
Hydroxyomeprnoie -C H~H_
H
o
II II o
- 5 - Omeprllole SUIlOM Fig. 3. Mc\abohsm or omcprazolc.
istmtion (Cederberg et al. 1989), The anti secretory
effe(;t of the drug, however, lasts much l onger. Omeprazole becomes selectively concentrated in parietal cells (Cederberg et aJ. 1989; Wallmark 1989) where it acts as a noncompetitive inhibitor of H +,K+·ATPase. Suppression of acid secretion is not correlated with plasma o meprazole concentratio ns, but there is an association between orneprazole AUC and anlisecretory effect (Cederberg c. al . 1989; Lind el 31. 1983). 3.4 Influence of Disease States on the Pharmacokinetics of Omeprazole
3.4./ Chronic Renal Failure The antisecretory effect o fomeprazole is maintained in patients with chronic re nal failure undergoing regular haemodialysis (Howden e1 at I 985b). In 6 s uch patients given omeprazole 30mg by mouth, time to peak plasma concentration , peak plasma concentration and AUe did not differ be· tween nondialysis and dial ysis da ys. The drug was not detected in dialysis fluid . There was marked interindividual variability in these pharmacokin· etic parameters. The range in AUe (138 to 3248 .IIg,lL· h) on the nondialysis day did not differ significantly from that in 6 healthy male subjects given a single o ral dose of 30mg (338 to 2270 .IIg,lL· h: Howden et al. I 9 84b). In the stud y by Naesdal et at ( 1986), 12 patien ts with established chronic renal failure (creatinine
clearance II to 62 ml/ m in) were given (14C)_ labelled omeprazole 20mg intravenously and 40mg orally in random order. The pharmacokinetics of orneprazole in these patienls did not differ significantly from values previously found in healthy subjetts. Mean elimination half-life was 0.6h, and mean systemic bioavai lability was 70%.
3.4.2 Chronic Lil'er Disease The oral and intra ve nous pharmacokinetics of omeprazole were st udied in 10 patients with ci rrhosis (McKee et al. 1988). Patients received orneprazole 10mg intravenously, and a 7-day course of IOmg orally. Acid secretion was low in these patients but omeprazole was still able to significantly reduce pentagastrin-stimulated acid output. The range of AUC(0-8) after the seventh oral dose was 3.97 to 10.61 .IImol/ L·h, again indicating a high degree of intersubject variability. The AUCs were higher than those recorded in a group of healthy male subjects given omeprazole I Omg orally for 7 da ys (Howden et al. I 985a). The mean elimination half-life was 2.85h, which was higher than that reponed for health y subjects. There was no evidence ofattu mulation of omeprazole in the ci rrhotic patients since no o meprazole was detectable in plasma at the stan of the study on the sevenlh da y of dosing. On the basis of these findings. specific dosage reduction is not necessary in patients with chronic liver disease. Doses of more than 20mg will not be needed in such patients.
Clinical
I'harmacolog~
ofOmcprazoi<"
Other re~archer5 have reported mean val ues for elimination half-life of 2.68h (Cederberg et al. 1989) and 2.85h (Rondanelli et al. 1989) in cirrhotic patients.
4. Drug Interactions Omeprazole can bind to hepatic cytochrome P450 and inhibi t the oxidative metabolism ofcertain drugs. This section reviews drug..
45
and mean elimination half-life was increased from 20.710 26.3 h (p < 0.01). The volume ofdistribution and protein binding of phenytoin were unaffected. In a separate study (Prichard et al. 1987), 10 healthy male subjects received. in random order. placebo or omeprazole 40mg daily for 9 days. Phenytoin 300mg was given ora lly on the seventh day of each treatmen\. Phenytoin AUC(O-72) was significantly increased by omeprazole from 121.6 to 151.4 mg/L ' h (p< 0.01). a finding which is of potential clinical importance in view of the narrow therapeutic index of phenytoin. There were nonsignificant increases in the peak plasma phenytoin concentrations and in the apparent elimination halflife. 4.4 Propranolol Omeprazole 20mg daily fo r 8days did not alter the pharmacokinetics of propranolol in a group of 8 healthy subjects taking propranolol 80mg twice daily (Henry et al. 1987). 4.5 Warfarin
4.2 Aminophenazone (Aminopyrine) and Phenazone (Antipyrine) Elimination of the 2 model drugs aminophen. azone and phenazone was measured in a group of healthy male subjects given omeprazole 30 or 60mg daily for 2 weeks b~ Henry et oIl. ( 1984). The values for both drugs were not significantly altered in su)).. jects receiving the lower do~. However. in 10 su)).. jects given omeprazole 60mg daily. the half-life of aminophenazone was prolonged by 21% (p < 0.05) and that of phenazone by 10% (p < 0.025). 4.3 Phen ytoin In 8 health y male subjects. the pharmacokinetics of phenytoin were studied before and after administration of omeprazole 40mg daily for 8 days (Gugler & Jensen 1985). The subjects were given phenytoin 250mg by intravenous infusion on each occasion. Phenytoin clearance was reduced from 0.025 to 0.021 L/ h/ kg after omeprazole (p < 0.05).
A group of 21 healthy male subjects received warfarin for 7 weeks in doses adjusted to reduce vi tamin K-dependent clotting factors to 10 to 20% of normal (Sutfin et al. 1989). For 2 weeks. Ihey were also given omeprazole 20mg daily. Omeprazole did nOI affect plasma concentrations of the S-enantiomer of warfarin but caused a 12% increase in those of the R-enantiomer. Thrombotest values were sl ightly reduced during the concomitant admin istration. from a mean of21.1% to 18.7% (p :: 0.04). No adjustment in warfarin dosage was required. It appears that omeprazole inhibits the hepatic metabolism of the pharmacologically less active R-enantiomer of warfarin , but (he effect was not great and is unlikely to be of major imponance. Nevertheless, funher studies are indicated. 4.6 Amoxycillin and Baca mpicillin The phannacokine(ics of oral amoxycillin 500mg and bacampicillin 800mg were studied in 8healthy volunteers before and after I week of omeprazolc
efm. Pharma('okmel. ;0 (JJ 1990
46
lOmg daily (Paulsen el al. 1989). Although there was a slight dela y in bacampicillin absorption. no significant effect was found on the AUe or elimination half·life of either amoxycillin or bacampicillin. 4.7 Nifcdipine In 10 healthy male volunteers, omcprazolc 20mg administered daily for 7 days significantly (p < 0.02) reduced the clearance ofnifedipine from 7S to 59.4 L/ h (Danhofct 31. 1989). Conversely, the clearance of omeprazole 40mg given intravenously was significantly reduced (p < 0.03) from 28.8 to 24.9 L/ h in the same subjects when they had been pretreated with niredipine IOmg 3 tim es daily for 5 da ys. 4.8 Antacids and Meloclopramide Concomitant administration of antacids does nOI affect the absorption of omeprazole (Howden & Reid 1988; Tuynman et at 1987). Similarly, there is no evidence for any interaction between orne· prazole and metoclopramide (Howden & Reid
1988).
S. Therapeutic UJeJ of Omeprazole 5. 1 Duodenal Ulcer Duodenal ulcer healing rates for antise<:retory drugs arc directl y related to their degree of suppression of 24-hou r in tragastric acidity (Jones et al. 1987). It is therefore not surprising that omeprazole has produced the highest reco rded healing ra tes in duodenal ulceration. The fi rst dose-comparalive trial (Gustavsson et al. 1983) fou nd a healing rale of I()()% after 2 weeks of treatment with omeprazole 60mg daily in 16 patients. A similar group of 16 pat ien ts was given omeprazole 20mg dai ly; after 4 weeks, the healing rate was 93%. Omeprazole has been shown 10 be superior to conventional doses of ranitidine in healing duodenal ulcers (Bardhan et al. 1986; Classen et al. 1985). H owever, a more reeent multicentre clinical trial from Canada fa iled to demonstrate a statis-.
tically significant difference in healing rates between omeprazole 20mg daily and cimetidine in the high dose of 600mg twice daily (Archambault et al. 1988). In an extensi ve meta.analysis of published clinical trials of antisecretory drugs in the treatment of duodenal ulcer (Jones et al. 1987). overall heali ng rates after 4 weeks of treatment with omeprazolc 60, 40, 10 and 20mg were 100% (n ::r:: 27). 98.4% (n = 126), 92.8% (n '" 154) and 95.5% (n '" 177). respectively. 5.2 Gastric Ulcer Omeprazole has been shown to be highly effective in healing benign gastric ulcers. In a detailed meta-analysis of published controlled trials of anti· secretory drugs in gastric ulcer (Howden & Hun t 1990). omeprazole was associated with the highest overall healing rates. In addition. a significant relationship was demonstrated between gastric ulce r healing rates and percentage suppression of 24-hour intragastric acidi ty. Walan el al. (1989) reponed that in a large multicentre trial omeprazole 20 or 40mg once dail y was superior to ranitidine 150mg twice daily in the treatment of ulcers of the body of the stomach or prepyloric ulcers. O meprazole 20mg daily for 4 weeks healed 69% of gastric ulcers in 203 patients; a dosage of 40mg daily healed 80% of gastric ulcers in 194 patients at 4 weeks. In 205 patients given rani tidine 150mg twice dail y, only 59% healed after the same period. Omeprazole was also shown to be highl y effective in healing gastric ulcers in patients receiving nonsteroidal anti-infl ammatory drugs (NSAIDs). In patients who con tinued to take NSAIDs, 81% of ulcers healed within 8 weeks of concomitant therapy with omeprazoie 40mg dail y. In a smaller study fro m Denmark (Danish Omeprazole Study G roup 1989), omeprazole 30mg daily was compared with cimetidine 200mg 3 times daily and 400mg at night in 161 patients with gas· tric ulcers. Healing rates after 4 weeks were 77% in the omeprazole group and 58% in the cimetidi ne group. The 95% confidence interval of the differ· ence between the 2 healing rates was from +4 to
Clinical Pharmacolos> or Qmrpr.lloit'
+34%.
mdicaling a rcal advanlage for omeprazole. II was also shOl·.. n Ihal omeprazole was superior 10 cimelidme in healing large gaslric ulcers. 5.3 Peplic Ulceralion RefraclOry Trealment
10
A high degree of efficac) has been shown for omeprazole in healing duodenal and gaslric ulcers "hu;h have failed 10 respond 10 adm inislralion of H2-rcccplOr anlagonisls. In 18 palienls wilh peplic ulcers refraclOry 10 prolonged Iherap) with Ihese agents. Irealment wil h onteprazo1c 40mg oncc dail y led 10 salisfaClOr) healing by 8 weeks in all patienls (Tytgat el al. 1987). Bardhan et al. (1988) sludied a group of 107 palients whose ulcers had failed 10 heal desplle daily Ireatment with cimelidine looomg or ranitidine 300mg. Paticnts were randomised eilher to con\lnue on their H ~-receptor antagonist or to rccei\(' omeprazole 40mg daily: in the grou p receiving o mcprazole 98% of ulcers had healed wilhin 8 weeks. whereas the heal ing ratt' in patients continumg on H~-receplOr antagOnists was 60%. The difference belween Ihe :1 treatmenls was highl) sigmficant (p < 0.01). Brunner et al. (1988) sludll:d Ihe efficacy of omeprazole in palients wi th unhealed gastric or duodenal ulcers after treatment for more than 3 months with ranitidine 450 to 600mg daily. Of the patients with gastric ulcer. 41 of 43 healed within 8 weeks on treatment with omeprazole 40mg dail y. In Ihe palients with duodenal ulcer, all II healed within 4 weeks with omeprazole 40mg dail y. 5.4 Reflux Oesophagitis Omeprazole has been shown to be highly effeclive in treating the symplOms o f reflux oesophagitis and in produci ng endoscopic healing of the lesions of oesophagitis. In the countTlCS "hcrt' omeprazole is currently licensed. reflux oesophagitis is recognised as one of ils prinCipal mdlcations. Omeprazole has bcen shown \0 dramatically reduce oesophageal acid exposurc in patients with this dlscase (Downton ct al. 1987: Klinkenberg-
Knol el al. 1988). Omeprazolc docs not affect lower oesophageal sphincter pressure (Denl el a1. 1989: Downlon et al. 1987). indlcatmg that its efficacy 10 treat 109 oesophagllis IS due solely to its suppression of gastric acid secret ion. OmepraLoic 20 or 40mg dally has been shown 10 be superior 10 placebo in healing reflux oesophagitis (Hetzel el .11. 1988) with veT) little diffe rence m healing rates between the 2 dose levels. Numerous trials have indica ted that the drug is superior to Hl-receplOr antagonists for this application (Blum el .11. 1986: Havelund et a1. 1988; Klinkenberg-Knol el a1. 1987; Vantrappen et .11. 1988: Zeitoun 1989). Omepra701c has also been shown 10 be particularl y effective for treating the more severe grades of oesophagi tis. where ils superiority o\'er the H1-receptor antagonists is even more evidenl (Bate el a!. (989). Unfortunately, relapse of ocsophagitis is very rapid after the drug is stopped (Dent el a!. 1989): in I study (Hetzel et a1. 1988). 82% of patients had relapsed within 6 months of SlOpping omeprazole. The question of long lerm mam lenance treatment of these paticnts with the drug has not yet been adequatel y ad· dressed. One brief report (Deviere el al. 1989) suggesls that omcprazo[e might induce regression of oesophageal columnar epithel ium in patienls with Barrett's ocsophagus. This very inleresting and polentially vcry important observation merits further study. and requires careful confirmat ion. 5.5 ZOllinger-Ellison Syndrome [l1Itlal case rcpons suggested tnat o meprazole Intgh\ be of conSiderable value in Ihe management of patlcnts "ith Zollinger-Ellison syndrome (Bianchi el a1.1982: Oberg & Lindstrom (983). Subsequentl). 1 senes nave confirmed this view. In the first (Lamers et a!. 1984).8 patients were studied after smg1c and repeated dosing "iln omeprazole. Smgle doses of omeprazole 80mg adequately controlled Ine gastric h~ persecrelion in most palients. 7 of .... hom were adequately controlled by continued omeprazo1e use and had endoscopic healing of all peplic lesions afler ..t "eeks of treatment.
48
Clln. Pharlnacokmf'l. 10 (I) 199()
In a review of the first 80 pat ients with Zollinger-Ellison synd rome 10 receive omeprazole (Lloyd Davies et at 1988), excellent control of basal gastric acid secretion and of symptoms was demonstrated. The median dose of omeprazo]e required was 60 to 70mg daily. and over 90% of patients were satisfactorily managed on doses below 120mg daily. There was no tolerance or lachyphylallis to continued o meprazole use, no further elevations i n gastri n levels and no obvious d rug-related effects o n laboratory val ues.
Allen J M. AdrIan TE. Webster J. Ho..~ A. Bloom SR. Effeel of sinal<'
d~
of oml'prazolc on .he pstroinlesl,nal IX'PI,dc
sponse 10 food. HCpalO-PSlroelllcrolOSY )1: 44-46. 1984
~
Andusson T. Ceder~~ C. Heudund A. lundoor'J P. Omcpra101e pharmarokinclics of sinaiI' and I'l:pealW ontt dally
ad min istration of 10. 20 and 40mg as ~nu~ric ('(Iated aranul«. Abstract. European Journal of Chmcal PharmacolOlY 36 (Suppl.): A 142. 1989 Archambault AP. Pare P. Baiky RJ . Na~en H. Williams CN. et al. Omepra~ok (lOmB dally) ve~us clmetldlnc ( l 200mg dilly) In duodenal ul~r healing and pain Rlief. GUtrocnterolOSY 94: 1130-1134.1988 Bardllan KD. Biaochl-POrro G . Bo$t K. Daly M. HlochclllTe RFC et al. A comparison of lWO dilTel"l:nt doses of omepralOlc vcr· ws rani tidil\¢ in treatment of duodenalulttr. Journal of ClinICal GaslrocnlerolOlY 8: 408-413. 1986 Ba rdhan KO. Nandal J. BIanchi-Porro G. Lazzaronl M. Hinch. clilTe RFC et al. Omeprazolc In lhe ll"l:almenl of I"l:fractory pepllC ule<:r. Abslract. GalilrocnlcrolOlY 94: A22. 1988 Ba le C M. Keeling PWN. O' Morain CA. WIlkinson SP. Mounl· ford RA. el al. Omepralole providcs fasler healing and symptom rtlief orrenu~ ocsopllaKitls than cimctidlne. Abstraci . GUI 302: AI49J..AI494. 1989 Blaochl A. Ddchler J-C Soule J..(". Payen D. Bader J·P. Control ofaculc Zolhn&<:r_Elhson syndrome wl lh Inlra"cnous omcpra_ zoic. Lane<:1 2: 122J..1224. 1982 Blum AL RiC("ker EU. Dammann t!G. Schlcssel R. l ux G. et al. Companwn of omcpralolc and ranllidine in lhe Il"l:almcnl of renu~ esophagitis. New England Journal of MedicIne 314: 716.1986 Brunner G. Cl"l:utlfcldt W. Harkc U. Lambens R. Th<:rap)' with omeprazo1c in patients wllh peplic ulceration rninantto highd~ ranitidine tl"l:atmen t. DiiC$lion 39: 8().90. 1988 Cederbc" C AndcT'Swn T. Skanbe"1. Omepralole: pharmacokinelics and melabolism in man. ScandinaVIan Journal of GaslrocntcrolOIY 24 (Suppl 166)' 33-40. 1989 Ching MS. MIhal)' GW. Angus PW. Morpn OJ. Devenish· Mcam S. cl II. Or;.1 bloovailabil1l Y of omcpralo1e bcfol"l: and afiN chronic therapy In duodenal ule<:r palienls. Bnmh Journal of Clinical PharmacolOlY. In press. 1990 Classen M. Dammann H-G. DomseHc W. Hullcmann W. londoni W. el al. OmepralOle heals duodenal. but nOI PSlnc. ule<:n more r.tpldly lhan ranilldlne. Hep:l1o-pstrocnteroloay 32: 24J..24!i. 1983 Clissold SP. Campoll·R.chard OM . Omepralole: a !)Khminary I"l:VICW of I1S pharmacodynamIC and pharmacoklnellC propertlCS. and lherapeul ic polcnllal .n pep"e ul~r disease and Zollln&Cr·Elhson s)·ndrome. Drugs 32: 15-47. 1986
DanhofM. Soons PA. van den Be" G. van Brummekn P. lanKn I BMJ. el al. InteractI ons bcl"'ttn nlfcdlplne and omepralolc. Abstract. European Journal of ClinIcal PharmacolosY 36 (Suppl.): A251. 1989 DanIsh Oml'pralo\e S ....dy Group. OmcpraZOIe and Clmelld'l\¢.n the tl"l:atmenl of uktn of thc bod)' of the slomach: doubleblind comparat"'e lnal. Bnll~h MedIcal Journal 298: 645-64 7. 1989 lXnl J. lIelzel OJ . Mackinnon MA . Reed WO. Nanelvala FM. E>alu3110n of omcprlllOIc In I"l:nu~ ocsopha,ltIs. Scand.navlan Journal ofGaslrocnterology 24 (Suppl. 166): 76-12.1919 lX~lere J. BUKt M. Oumone<:au J-M . RIchert F. CRmer M. RC"&Rsslon ofBarrel1's epllhehum wllh omepr;tzole. New En,land Jo urnal of Medicine 320: 1497-1498. 1989 Do,,·nton J. Dent J. Hedd1c R. cl al. Elev.tlon of pSI rIC pH h<:al$ pePIlC OCSOphallllS - a rok for omeprazok. Journal ofGutroenlerology and H~p.atoloay 2: 317_324. 1987 F«len IIPM . Tu ynman II ARE. lXlizc J. Frants RR. Straub J P. CI al. EIT«I of s.n&ie and I"l:pealed doses of oral omeprazole on gaslrlc aCId and pepsin scc:retlon and faSling Krum gastrin and scrum pepslnOlCn I levels. 01&CSIIV( OiKa5cs and Scicnc<:s 31: 361·566.1986 GU8ler R. JenKn JC Omepralole inhIbIts ehmlnatlon of dilllepam. Lane<:1 I: 96. 1984 GUller R. JenKn Je. Omepralolc inhIbIts o~ldat"·( drug metabolism: smdlo .... lIh dlal~pam and phen)·tOln In v,,·o and 7· ethmyroumann in Vllro. Gamocnterology 89: 1235·124 1. 1985 Gusta"sson S. AdamI H-O. loaf l. N)'be" A. Nyren O. Rapid ilo:ahnl of duodenal ulttrs WIth omepr.tlok: double·bhnd d~_ comparative lrial. Lancet 2: 124-125. 1983 Ha.. elund T. Laurstn LS. SkoubQ.KnSlenKn E. Andersen BN. Pedersen SA. el a1. Omcpralolc and ranitidlne III ll"l:almenl of RnU~ OCSOpha8111S: double blind comparali"e trial. British Med,cal Journal 296: 89-92. 1988 Ilenry OA . SomervIlle KW. Kllchingham G. Lanlman MJS. Omeprazolc: clT«t$ on oudail~e drug metabolism . Bntish Journal ofChmcal Pharmaroiosy 18: 195-200. 1984 Henry O. Brent P. Whyte I. MIhaly G.lX'·cnlsh·Meal"l:s S. Propranolol sleady-stale pharmacoklncllcs al"l: unaltered by orne· pral.olc. Europe,... Journal of ClinICal Pharmacoiosy 33: 369· 373. 1987 Hetzel OJ . Denl J. Reed WD. Nanelvala FM. Mackinnon M. CI al. Heahng and I"l:lapSC of KVcre pepllC esophall\lS after tl"l:at· mcnt .... ,th omeprazoJc. Gasll"O('nleroloay 95: 903-912. 1988 lIo .... den Cw o Beastan G t! . RCld Jl. An In"esllgaIlOn IIIto Ihe dT«lS of omcpralOIc on rcnalmbular funClIon and cndocnnl' function III man . Scand"''''lan Journal ofGaslrocnlcrolosy 21 (Suppl. 118): 169.1 70. 1986b Ho .... den Cwo Derodra J K. BUIJCI DW. Hunt RH. EITCCIS of 10"" doS<" omcpl1lzok on gaslnc SCC:Rllon and plasma pSlrin in pahenls .... ilh healed duO of SIngle and Rpealed OOS<"S of omcpr.tlOIc on liStriC acid and pePS'" scc:relion In man. Gut 23: 707-710. 19843. Howden CWo ~I unl Rfi. The Rlalionshlp bet""ccn supprtSSlon of aCldlly and gaSlnC ule<:r heahna r.t ICS. Ahmentary PharmacolOSY and Th<:rapeull<'5 4. in pms. 1990 1I0wden CWo Ken yon CJ. Beaslall Gli. ReId JL Inhiblilon by omepralole ofadrenoronicalo:sponK 10 ACTH: clinical sludICS and c~penmcnls on bo"lne adl"l:nal conCA In Vllro. ClInIcal Sclene<: 70: 9<;1·102. 1986c Howden CWo Mercdllh PA. Forl"l:st JAH . ReId JL Oral pharmacokInetics of oml'pralolc. European Journal of ClInIcal Pharmacolosy 26: 641-643. 1984b
Chnlcal
l'h a rmaC'Olog~
of Omeprazolc
(\\. P""lon (" D. \k,,'dnh I'~. lIught~ !) \'.\ . \' a<. doupU .\1. "1 al .\nll'l«rc:IOf) df,'t"1 ... nd or.>1 plla'mKo~ m· Clin 01 UmcllralOle In pallenl~ ",,,11 cllmn" ,enal fal'u'e Eu'opo::~n Journal ofehnl",1 PharmawlO$) ~8 1>.17-640. 1985b t' o"den ( \\. ReId J l Orncpr.Iloic, a 1"'1"" 'plOlOn pump In· 111\>110" la(· ~ of .-ITecl on rc:nal handling of ck("lIol)lc~ and urlnar) a,·,d,f,callon EU'OP'o'an Journal ul ClinIcal Pharma· ("oi()J) 2~ 619_f>..IO. 19S4 lI o.-dcn ('" RCld J I Th,' dTC'C. of anlaCl'!. and mrtoclopr.>· mlde on omcllr.illolc aMClrp1l0n and dl'~lIlon K"'I~h Jour· nal of( ',n,nl Pharma,'olog} ~5 1~9.7111 19~~ Jon.:,I)B I' o"o.lcn ('\\. Bur"". 0 '" " err (. 1), lI un. RII .\nd Wpprc'Hlon In dllOn 'I) ndrome [ 1T«1' of a .. nile dOloC and of lonl''''rm Ifealmenl In p:l1I~nl! rOI.lanl 10 h"lamlnC 1I :-m:t'pU)r anlaaonl~s.. '.; ('Y. England Journal of Mrol(1l1(' 11(1, H8·7111 1984 Lan/on· \I ,lkr S Pounder RE. Hamli ion \ IR RIll \ (hrollOlo , ... r. CI ~I T"'cnl,·four·hour ,"U';lp~I"" ~",dl1) and pla.m~ g;1\lnn '·OOCl,'nlr.>lIon belorc: and du"nllrc:alm~nl ""th "l1hcr ",nllldlll(' Of omcl'""ok .... ,Imcnla~ Ph;lrln\'Ok\s\ and The",· po::uuc> I ~19·~51 1'I8~ LInd T .\ndcn.'>On r ')~an""flI. I. Olbe [ Hlhal) ,'\( r~llon of [I~I-omep'a/okln human; (I,n,,·al f'harma(oIOC' and Thc",· I'<'U II<\ 4 ~ XlJ ·SUS I'I~~ lInd T. (cd,·rbo.'rg { Hcn,,'d G. It aglund 11. Olt... I rlT,xl uf omepra/ok - a &a.lnc proton pump ,n h,bllor _ on po::n lap'. IIIn"lImu13lcd aCId \oC("'\lon In man. (; ul 14 !7t).:'II. 198.1 Llo,d· l>a\le; .... . \ Ru1Ien.'>On .... . Sol,ell L Omepra/ok In Ihe Irc:almen. ofZolhngcr·Elh'>On~) ndrome a 4·)ear Inlcrnallonal ,'ud, \ hmcn .al) f>harma.-oIOl~ ;lnd Ther.>peullC>: 1.1•.1: 1'188 \1 a,(,,'~hll'l .\J Ito"'ocn C\\ .... cn\on (1. &a,.all (j H. R ~ld J l Thc ~ff''CI; of omel'''''oIc on ~ndocllnc (un,·lIon In man ! urop.-an Journal o((llnl(;l1 Pharmxolog) 3~ J:3·4H. 198' \I , .... ..... R!- \l aC<;,khn,1 ~J, Garden OJ. forrc:l.1 J-\f~ . Caner IX TIM' anll''o('("rCIOf} eff«1 ~nd pharmam~IRCII(\ of orne· pr,l/ok In ,hrom" hon R. Rcgjrdh ('.G. CI al l'harm"co~lncllC' o( I'~q·omcpra /ok In pallen l. "' lIh Inlp:llfcd "'nal fu,'nllon Chnlcal f'harmacoIOl) and T h,·",. po::u ll n J(} 144. 151 19~/:I ' aclodal J, Rln ~cl \I Rodcmar G, Gouhard R, Lund Q ul~1 G. el 31 TIM' cff«1 of 10m, omcpraf<)lc dall~ on lofrum psmn. ~ 4. h Inlr.lp.,,,C ."d,l< and b,1e aCId con«nlrallon In duodenal uker palICn.S 'in.nd,na',an Journal of (;as. rocnlnoiot) ~~; ;.I~ 1'1&7 Obc'l .... LIndstrom tl RedUCllon of pstrlC lI)per.«rc:1I0n In Zolhngcr.(lhwn s)nd.omc "'1111 omepnl/ok" U ft«1 I /:16.67. 1'183 Paullofn O. tl oalund P \\. alder \I ' 0 cff«1 of omcP<1l~olc·' n· duccd h)t)OaCld ll) on I1M' blo;c<31Iablhl) ofamo~ )Cllhn or ba· .... mIlICllhn. Scotnd lna" an Journal of I n f«lIOu~ O,!oCaJon 21 11'1·~~3. 198'1 Pnellard PJ , Y,a ll RP. Kl1chlnl man G .... Somcf\1I1c KY" Lang. man MJ S Oral phen) lom ph armaW~ l nC IlCS during o mcpra· Ho"'d~n
lol" .IM'",P) Hm"h Juurnal of(l," ,(al PharmMOlos) 24 543· 545. I'ln Prichard pJ . ' coman< r-. D , \h hal) G\\ Jonc, OH , H uc ~lc pJ. Cl al Onlcpr.llolc .. ,wd) of InhIbItion of &a\lnc and oral pharnl~CO~ IOCIIC> ahrr mornln8 or "upp[ lOll! 7'1.'I ~ 198j Rnndanelll R R\'giI/1I \1 Cerum R ClSlcrnlno \\, S"clh R. e• al l'harmaco~lnCIIC> of omepra/o,e In pallents "',IIII"er dl~' C3"': \1>0.1<3.;, [urOfIC~n Jou rnal of ClInl("31 I'harnlaColOS) 36 (Suppi t \ ito. [9S'l \al"h~ G, "'a llmar~ .. T he &aslne fI' . .... ·-.\Tpa sc Ihc SIIC of aClIon of omcp"'lOlc Scandlna'lJn Jour nal of ( ,a 'lrcxnlcr . 010$) ! 4 ISuppl 1M) 3· 11. )989 Sh arma ....... Sanlan a [ \ \\ ood [ C Wah RI' I'c"crJ M . CI 31 [mrag.Ulnc bactenal aCI" 11) and n,lro!.:lIlOn beron'. dUfl n&and afll" l",aln,,'Ol ""Ih omcpra folc 8"II.h \l cdl<'al Journal ~89 717.7IQ. IQS4 SUlfin 1 Balmcr .... 8o~lrom Ii Er,~~wn S lI oglund f', CI al Slcrr'n and ek"lrol)IC~ aftcr omepra/ok ~Onll and 4(1m1 dall~. (ju, !6 1U1&.JI1~ 4 1'1115 Tu)nman ll ·\ RI I C\lcn H f' \I Roh's .... \ 1cu""~\('n'>(; M Lac~ of dh'Cl of anlaCld< on pla~ma cun(Cn1r.nlon~ of omcpl'lllok I''''n n \'n!,'IIc-("oalcd I"IOulo. Hnllsh Journal of ClinIcal PharmJ,nll)J< 2 ~ ~H·835. 1'1&7 T ~lg;tl ( .' J . L:IOlcr, (HII'" Ib me" leman \\ Janlo\'n JMIIJ . \\ I\\on J.\ OOl"pla/ok In P'o'plle ~kcr, r~~,, ' an l 10 h"lanun,· H ··"·""p.or anlaIOn"l~ .\ hnlcnt~ I'harmamlOC\ and Thcr· 311<'UII" I 31·)8.1987 llk~ RJ \\ "Chl R Ik a'iall G Il Caner IX' 'I hc eiT.... 1 ofom,,pra/oic on In~uhn_lndllCed 13.ln, M"Crcllon 10 man ScOI1IM1 MOOKal Journal )0: %-100. 198j \ an.r.>ppo::n (; RU1an'n, L. S,.-hurmans I' Ccxl)ra,II,s J·l Ornepra/olc ,"Ilml) I~ supo::"or 10 rar ••• d.1>(' In ShOn·lerm Irc:a.· menl of UlcC"'I"C rdlu , nophJMIIIs. 0 1101"(" I)'",a~~ and XI"1Kn H 5nj~9 1988 '" alan ... Ibdcr J P (Ia,....:n \1 !...:lm(rs C BII\\ p.pcr D'" el al EIT,'·I of omcpr.>/ok and ",nludlnc on ulcer huhnl and rc· lap", r.>1<" In pallenl, "', Ih b.'nlgn g;t~1nC ukcr '.; ,.'" England Journal 0\ \ledleln,· l~O 69. '5. IQ8'1 \\ allmar~ K On1<·pra/olc. mode OfaCIlOn an d effcci on aCld !oC' c,,'lIun In an,mah \ <; andlOa' Ian Journal of Ga ~l ro.: nlcrolos~ "4 I\uppl I~t>l 12·18. 1989 \\ all RI' Gomn \l dc !-~ "' ClOd E( logan III I'ounder RE Eff...o of dal" 0",1 omellB/ok on " ~ hour ,nl"'p,mc ac,dll) Bnmh \l edlc~1 Journal ~~1 12.I J [983 \\. olfe \1\1 \o1l.\ H I1M' phHloIOS) of pm,c 3<1d lo<'ere\lon ,~'" En,.Iand Journ31 of \l edKIIH' 119' '701·171~. 1988 ZClloun I' (omp.anloOn of oltlC'pr.l.lOlc "' lIh n.nllldlll(' In chc lrc:almcnl of rc:Au\ OC.opllall\llo. ScotndlOa
II.
I"
('orr"'pClnocnC\' and rc:pnnlS Or ("'~/rl II 1/,,"dr1l. lI n "~rSII) IXpanmcnt of \ kdlCln,· and Ther.>po::ullC!o. Gardmcr In, IIIUIC "' e<; lern In!irma!). ( ,la!ogO" Gil /:II\ T. Scolland
