D. Brian Jones

Omeprazole: A Study of Its Inhibition of Gastric pH and Oral Pharmacokinetics After Morning or Evening Dosage

Pharmacodynamic and pharmacokinetic studies of omeprazole, a new gastric antisecretory agent, were undertaken in 8 healthy subjects. The drug was administered orally as an encapsulated enteric-coated granulate (40 mg daily at 9 am or 9 pm for 5 days), and its effect on the integrated 24-h gastric pH was determined, together with its apparent bioavailability. The pretreatment 24-h median pH was 1.9 (interquartile range 1.4-2.9). After 5 days of treatment, the median pH had risen to 5.0 (3.7-6.0) (p less than 0.01) with morning dosage and 4.5 (3.0-5.6) (p less than 0.01) with evening dosage. This corresponded to a greater than 99% reduction in 24-h median hydrogen ion activity, with morning dosage having a greater effect (from 9 am to 8 pm) (p less than 0.01) than evening dosage. The relative bioavailability of omeprazole increased twofold from day 1 to day 5 of treatment with morning dosage (p less than 0.02) and threefold with evening dosage (p less than 0.02), suggesting that increased absorption of this acid-labile drug occurs with increasing inhibition of acid secretion. We conclude that this formulation of omeprazole presently being used in clinical trials is a highly potent antisecretory agent in humans, although its optimal effect may not be observed for several days.

Effect of plasma protein binding on elimination of taurocholate by isolated perfused rat liver: Comparison of venous equilibrium, undistributed and distributed sinusoidal, and dispersion models

In the past, various models have been developed to allow better characterization of the hepatic elimination of substrates from plasma. In this study we investigated the applicability of the venous equilibrium, undistributed sinusoidal, several distributed sinusoidal, and dispersion models to the steady state elimination of sodium taurocholate by the isolated perfused rat liver. Rat livers were perfused with 24-14C- taurocholate (sodium salt) at a concentration of 25 μM (specific activity 500 μCi/mmole) in a single-pass design (n=7) or at a rate of 0.5 μmol/min (specific activity 40 μCi/mmole) into the portal vein in a recirculating design (n=5). In single-pass experiments, the changes in hepatic venous outflow concentration (C0) with changes in unbound fraction of taurocholate (fu) from 0.09 to 1.0 were fitted better by the venous equilibrium model, by the dispersion model, and by a distributed model in which heterogeneity in both hepatic blood flow (Q) and intrinsic clearance (CLint) was defined by separate density functions. The very large value of dispersion number (Dn>107) yielded by the dispersion model is consistent with a high degree of axial mixing of blood within sinusoids. The large coefficients of variation (0.7–232) for the density functions describing the transverse heterogeneity of Q and CLint obtained with the Q/CLint -distributed model were consistent with a large degree of heterogeneity in Q and CLint within the liver. In recirculation experiments. the steady state unbound concentration of taurocholate in the reservoir (Cuss) was independent of fu (range 0.05–0.9). This finding was not predicted by the undistributed sinusoidal model, but was in keeping with the venous equilibrium model, with the dispersion model, and with the Q/CLint- distributed model. Therefrore, there is no need to invoke cell surface-mediated dissociation of albumin-ligand complexes in hepatic taurocholate uptake. As the dispersion and Q/CLint- distributed models are conceptually plausible and operationally accurate, it may be time to relinquish the venous equilibrium model, which, though operationally accurate, is conceptually flawed.

Early Use of Thiopurines or Methotrexate Reduces Major Abdominal and Perianal Surgery in Crohnʼs Disease

Background:Earlier introduction of immunomodulators (IM) thiopurine or methotrexate is advocated to improve Crohns disease (CD) outcomes, but whether abdominal surgery can be prevented remains controversial. Methods:A specialist-referred cohort of CD was recruited from 1970 to 2009. Early IM use was defined as commencement of azathioprine or methotrexate within 3 years of CD diagnosis and adherence of at least 6 months. Propensity score matching was conducted to correct for confounders influencing early IM introduction. Outcomes of interest were rates of initial and recurrent major abdominal surgery for CD and their predictive factors. Results:A total of 1035 consecutive patients with CD (13,061 patient-years) were recruited. The risk of first and recurrent major abdominal surgery at 1, 5, and 10 years were 17.5%, 28.4%, and 39.5% and 5.9%, 19.0%, and 33.3%, respectively. Early IM use increased over time from 1.3% to 55.3% (P < 0.0001) and was a significant independent predictor of lower rates of initial abdominal surgery (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.35–0.69), recurrent abdominal surgery (HR, 0.44; 95% CI, 0.25–0.79) and perianal surgery (HR, 0.30; 95% CI, 0.16–0.56). Using propensity score matching, early IM significantly reduced surgical rates (HR, 0.54; 95% CI, 0.37–0.79). Number needed to treat to prevent a surgical event at 5 years from diagnosis and after initial surgery was 6.99 (95% CI, 5.34–11.95) and 8.59 (95% CI, 6.26–23.93), respectively. Conclusions:Early IM use with thiopurines or methotrexate was significantly associated with the reduced need for abdominal and perianal surgery in CD.

Effect of hypoxia on oxidative and reductive pathways of omeprazole metabolism by the isolated perfused rat liver.

The effect of hypoxia on the elimination of omeprazole, a potent inhibitor of gastric acid secretion, was studied in the isolated perfused rat liver. During normal oxygenation, a 10 mg bolus dose was eliminated rapidly (T 1/2 beta = 8.0 +/- 1.1 min; mean +/- S.E.M., N = 4), while under hypoxic conditions T 1/2 beta was increased to 81.6 +/- 5.4 min (P less than 0.01). Upon reoxygenation, T 1/2 beta returned to 9.6 +/- 1.3 min. During hypoxia, perfusate concentrations of an oxidative metabolite (the sulphone) were reduced by 68%, while those of the reductively-generated sulphide increased 4-fold. With reoxygenation, both formation and elimination of the sulphone were increased, while the sulphide, which had accumulated during the hypoxic period, was eliminated rapidly. These findings were duplicated in steady-state experiments, in which omeprazole clearance during hypoxia fell by at least 70%, and sulphide concentrations in perfusate rose from undetectable levels to 200 ng/ml (at least a 10-fold increase). Sulphone concentrations did not change with hypoxia, consistent with a reduction in both its formation and elimination rates. We conclude that the hepatic elimination of omeprazole is severely retarded by hypoxia, but that this effect is promptly reversed by reoxygenation. The increased formation of reductive metabolite during hypoxia is not of sufficient magnitude to sustain the normal hepatic elimination of omeprazole.

Effect of omeprazole and polyethylene glycol-400 on antipyrine elimination by the isolated perfused rat liver.

The effect of the substituted benzimidazole, omeprazole, a potent inhibitor of gastric acid secretion, on the hepatic elimination of antipyrine was studied in the rat isolated perfused liver. Bolus dosage (10 mg in 100 ml perfusate) and infusions (1 μg ml−1 perfusate concentrations) of omeprazole in its solvent, polyethylene glycol−400 (PEG−400), reduced antipyrine clearance by approximately one third (P < 0·05). PEG−400 alone caused a 15% decrease in antipyrine clearance (P > 0·10), indicating that the effect seen with omeprazole was at least partly due to the vehicle of dissolution. A significant but mild choleresis was noted in all preparations (P < 0·01) exposed to PEG−400. We conclude that the effect of omeprazole on hepatic drug elimination in patients warrants further study.

Morning or Evening Dosing with Low-Dose Omeprazole: Effects on 24-Hour Gastric Acidity Profiles in Duodenal Ulcer Patients

Previous studies with omeprazole have demonstrated that a daily dose of 30 or 40 mg reduces the acidity of gastric contents throughout the 24-hour period (1, 2). The influence of dosing time has been examined with 40 mg given either in the morning or in the evening (1). A dose at 0900 hours produced a slightly greater overall elevation in 24-hour pH than did dosing at 2100 hours. Inhibition of gastric acidity was nearly complete with either regimen, so that the difference between them was of doubtful therapeutic significance. At a lower dose, which may be considered for maintenance therapy, the time of administration may be more important. Therefore, 24-hour gastric pH profiles were examined in duodenal ulcer patients given omeprazole, 10 mg, in the morning or the evening.

Double-Blind Comparison of Omeprazole, 10 mg Versus 30 mg, for Healing Duodenal Ulcers

The optimal dose schedule for omeprazole in the treatment of peptic ulcers has not been established. Two recent comparative dose studies in small groups of patients showed rapid healing of duodenal ulcers treated with 20, 40 or 60 mg/day for 4 weeks (1, 2). We report a double-blind study comparing a lower dose of omeprazole than has previously been studied (10 mg/day) with an intermediate dose (30 mg/day).

The inhibitory effects of ranitidine and Cimetidine on propranolol elimination by the rat isolated perfused liver

The effect of low (50 μg) and high (1 mg) doses of the histamine H2‐receptor antagonists cimetidine and ranitidine on the first pass extraction of propranolol was studied in the rat isolated perfused liver. Both low and high dose cimetidine increased the area under the perfusate propranolol concentration time curve (AUC) 4 to 5−fold. Although low dose ranitidine did not alter propranolol AUC, high dose ranitidine increased it to the same extent as cimetidine. These results indicate that ranitidine has a clear propensity for microsomal inhibition, but one which is unlikely to be manifest at therapeutic dosage.