Effect Of Gastric pH Research Articles

Comprehensive clinical pharmacology characterization of AZD4635 in healthy participants to support dosing considerations.

Two phase 1 studies characterized the oral bioavailability of AZD4635 (potential anticancer therapy) and factors that may influence its pharmacokinetics (PKs; food, smoking, proton-pump inhibitors [PPIs] and CYP1A2 inhibitors) to support continued clinical development of AZD4635. Study 1 (comparative PK study; nonsmokers) consists of Part A and Part B. Participants (fasted) in Part A were administered 50 mg of AZD4635 either as nanosuspension or capsule. In Part B, these participants were administered a 50-mg capsule either following a high-fat meal or with a PPI in the fasted state. In Study 2 (CYP1A2 mediated drug-drug interaction study), a 25-mg AZD4635 capsule was administered to smokers and nonsmokers (fasted) with or without 100 mg of fluvoxamine. In Study 1 (N =21), AZD4635 exposure was comparable between the capsule and nanosuspension. The high-fat meal produced a 12% decrease in AUCinf , a ≥50% reduction in Cmax and delayed absorption (Tmax : 4.0 h vs 1.5 h) for the capsule. The PPI did not affect the oral bioavailability of the AZD4635 capsule. In Study 2 (N =28), AZD4635 + fluvoxamine (compared with AZD4635 alone) produced ~5-fold increases in AUCinf , 2-fold increases in Cmax and prolonged AZD4635 elimination half-life in smokers (22.7 vs 9.0 h) and nonsmokers (22.4 vs 9.2 h). All treatment regimens were well tolerated. The most common adverse events included dizziness, nausea and headache. The high-fat meal reduced the rate but not the extent of AZD4635 absorption. The effect of gastric pH on AZD4635 was minimal. Smoking had no effect on the exposure (Cmax and AUCinf ) of AZD4635, while fluvoxamine increased AZD4635 Cmax and total exposure. No new safety concerns were identified.

Effect of gastric pH and bile acids on the survival of Listeria monocytogenes and Salmonella Typhimurium during simulated gastrointestinal digestion

The human gastrointestinal tract (GIT) harbors numerous defensive mechanisms to impede pathogen colonization, including gastric acidity and bile acids in the small intestine. This study aims to elucidate the survival of Salmonella Typhimurium and Listeria monocytogenes under different levels of gastric pH (2.0–3.5) and bile acid concentrations (2.5 mM – 10.0 mM), during an in vitro digestion process following the ingestion of a contaminated food model system. The results showed that S. Typhimurium was more susceptible to gastric acidity than L. monocytogenes, yet more bile acid tolerant. Interestingly, the bile acids bactericidal effect towards L. monocytogenes was higher if the previous exposure to the gastric acidity was harsher. Our findings suggest that, despite the different microbial behavior of the two species in the simulated GIT, the effects of gastric acidity and bile acids alone could not prevent their survival in the intestine. Industrial relevanceS. Τyphimurium and L. monocytogenes represent biological threats that are of major concern for the food industry due to their ubiquitous nature and their ability to trigger foodborne illnesses. Their ability to survive the gastrointestinal passage is crucial for their subsequent intestinal colonization that can lead to host infection. Therefore, obtaining a deeper insight into the factors affecting pathogen survival in the gut is vital for the establishment of more efficient strategies to prevent foodborne diseases. Given the limitations and ethical constraints of conducting studies like this in vivo, the applied in vitro digestion model system along with the mathematical modelling can provide a valuable alternative that can be readily utilized in the food and pharmaceutical industry as a platform for similar digestion studies.

Effect of gastric pH and of a moderate CYP3A4 inducer on the pharmacokinetics of daridorexant, a dual orexin receptor antagonist

Daridorexant is a dual orexin receptor antagonist developed for the treatment of insomnia. The solubility of daridorexant is pH-dependent and daridorexant has been shown to be a sensitive CYP3A4 substrate when co-administered with moderate CYP3A4 inhibitors. The purpose of this study was to assess the effect of an increased gastric pH on daridorexant pharmacokinetics (PK) and the extent of interaction when daridorexant is co-administered with a moderate CYP3A4 inducer. In this prospective, single-centre, randomized, open-label study, 24 male subjects consecutively received four treatments, i.e., daridorexant 50 mg single dose; famotidine 40 mg single dose + daridorexant 50 mg single dose; efavirenz 600 mg once a day (o.d.) for 10 days; and daridorexant 50 mg single dose + efavirenz 600 mg o.d. for 2 days. Plasma PK parameters of daridorexant were derived by noncompartmental analysis. Standard safety and tolerability evaluations were analysed descriptively. When daridorexant administration was preceded by administration of famotidine, daridorexant Cmax decreased by 39%, geometric means ratio (GMR) (90% confidence interval [90% CI]): 0.61 (0.50, 0.73). AUC0-∞ remained unchanged. In the presence of steady-state efavirenz, daridorexant Cmax , AUC0-∞ and t½ decreased by approximately 35% (GMR [90% CI]): 0.65 (0.54, 0.78), 61% (0.39 (0.348, 0.44), and 35% (0.65 (0.58, 0.73), respectively. tmax remained unaffected. All treatments containing daridorexant were well tolerated. Daridorexant 50 mg can be administered concomitantly with gastric pH modifiers or with moderate CYP3A4 inducers without dose adaptation based on efficacy observed at lower doses in Phase 3 studies.

Computational Insights into the Effect of Gastric pH on the Stability of Apo-Lactoferrin and Its Interactions with α-Lactalbumin and β-Lactoglobulin

Lactoferrin (Lf) is increasingly of interest in the food industry due to its significant health benefits. In order to preserve its functional properties under various processing regimes, whey protein isolate (WPI) has been proposed as an encapsulant. Recent studies have elucidated the stability of Lf and WPI, and the complex formed between these at food processing temperatures. However, the effect of simulated gastric conditions has not been evaluated. Accordingly, the objective of this study has been to investigate the behaviour of apo-Lf, the least stable form of Lf under gastric pH conditions using molecular dynamics simulations. This was extended to interactions with α-lactalbumin (α-La) and β-lactoglobulin (β-Lg), two of the primary constituents of WPI. The data show that at the acidic pH, apo-Lf has weaker interactions with both β-Lg and α-La, compared to those at neutral pH. Nevertheless, free energy calculations for protein-protein dissociation using umbrella sampling indicate that intermittent contacts are maintained between apo-Lf and β-Lg units, resulting in a broad energy minimum point at intermediate distance, possible flocculation composed of protein particles, and eventual gel formation. This property may be exploited to entrap further bioactive components within the protein matrix for novel engineered food materials. Per-residue evaluations at a range of distances between apo-Lf and β-Lg units were also calculated. The results indicated a reduction in the movements of most residues with decreasing separation, highlighting those residues whose motions are most sensitive to inter-protein distance and may play important roles in sustaining long-range interactions. Overall, this work demonstrates the advantages of in silico methods as novel tools in understanding the structural changes of apo-Lf and the interaction with α-La and β-Lg that may benefit future development of nutraceuticals.

The Effect of Gastric pH on the Pharmacokinetics-pharmacodynamics of Naphthoquine in Rodents, as well as in Human Predicted Using a PBPK Model.

Fixed-dose combination of artemisinin and naphthoquine (NQ) is a new artemisinin- based combination therapy for the treatment of uncomplicated Plasmodium falciparum. NQ absorption has been reported to be affected by food in humans. The effect of gastric pH on NQ pharmacokinetics and antiplasmodial activity was investigated. The pharmacokinetic profiles of NQ were studied in healthy rodents after an oral dose of NQ with or without gastric pH modulators, i.e., pentagastrin (stimulator) and famotidine (suppressant). The effect of gastric pH on NQ exposures in humans was predicted using a physiologically-based pharmacokinetic (PBPK) model. The effect of gastric pH on the antiplasmodial activity of NQ was evaluated in mice infected with Plasmodium yoelii. Neither pentagastrin nor famotidine affected NQ absorption (AUC0-t and Cmax) significantly (P > 0.05) in rodents. The predicted PK profiles of NQ in humans did not show an effect of gastric pH. Compared to pure NQ (ED90, 1.2 mg/kg), the combination with pentagastrin showed non-significantly (< 1.5-fold) higher antimalarial potency (ED90, 1.1 mg/kg). Correspondingly, the elevation of gastric pH (up to pH 5) by famotidine treatment resulted in a relatively weaker antimalarial potency for NQ (ED90, 1.4 mg/kg). Such a difference is within the acceptable range of variability in NQ pharmacokinetics and antiplasmodial activity. Although the food was found to significantly impact NQ pharmacokinetics, other factors except for gastric pH should account for the result, and the warning of careful use of NQ in patients with the acid-related disease is not expected to be clinically meaningful.

Effect of gastric pH on erlotinib pharmacokinetics in healthy individuals: omeprazole and ranitidine.

The aim of this study was to evaluate the effect of coadministration of acid-reducing agents on the pharmacokinetic exposure of orally administered epidermal growth factor receptor inhibitor erlotinib, a drug that displays pH-dependent solubility. Two studies were conducted, the first with the proton pump inhibitor omeprazole and the second with the H2-receptor antagonist ranitidine. Twenty-four healthy male and female volunteers were enrolled in each study. Erlotinib was administered as a single oral 150 mg dose on day 1. After the washout a subsequent study period evaluated 150 mg erlotinib administered with the acid-reducing agent. Omeprazole (40 mg once daily) was given on days 11-14, concomitantly with erlotinib on day 15, and for two additional days (days 16-17). In the ranitidine study, on day 13, participants were randomized to either concomitant dosing (treatment B) or staggered administration (treatment C) of erlotinib and ranitidine and crossed over to the other treatment starting on day 27. For treatment B, ranitidine (300 mg once daily) was administered in the morning for 5 days, 2 h before erlotinib. For treatment C, ranitidine was administered as a divided dose (150 mg twice daily) for 5 days, with erlotinib given 10 h after the previous evening dose and 2 h before the next ranitidine morning dose. Plasma samples were obtained for determination of the concentrations of erlotinib and its metabolite OSI-420, following each erlotinib dose. All participants were monitored for safety and tolerability. The geometric mean ratios of AUC0-∞ and Cmax for erlotinib and AUC0-last and Cmax for OSI-420 were substantially decreased when erlotinib was dosed with omeprazole. The estimated mean ratio (90% confidence interval) for erlotinib was 0.54 (0.49-0.59) for AUC0-∞ and 0.39 (0.32-0.48) for Cmax. For OSI-420, the estimated mean ratio was 0.42 (0.37-0.48) for AUC0-last and 0.31 (0.24-0.41) for Cmax. AUC0-∞ and Cmax for erlotinib were substantially decreased by 33 and 54%, respectively, upon coadministration with ranitidine, but the decrease was only 15 and 17% when ranitidine and erlotinib were given staggered. Similar results were observed for the metabolite OSI-420. Erlotinib was generally well-tolerated alone or in combination with omeprazole or ranitidine. Erlotinib pharmacokinetic exposure was substantially reduced upon coadministration with omeprazole and ranitidine, but not when administered with a staggered dosing approach to ranitidine. Therefore, it is recommended that the concomitant use of erlotinib with proton pump inhibitors be avoided. If treatment with an H2-receptor antagonist such as ranitidine is required, erlotinib must be administered 10 h after the H2-receptor antagonist dosing and at least 2 h before the next dose of the H2-receptor antagonist.

Effect of Gastric pH on the Bioavailability of Albendazole in Rabbits

The effect of gastric acidity on the bioavailability of albendazole, used for treating human echinococcosis, was evaluated using gastric-acidity-controlled rabbits in a crossover manner. The normal gastric-acidity group, which had a gastric pH of around 1, showed threefold greater bioavailability than that of the low acidity group, which had a gastric pH of greater than 5. However, in solubility studies, albendazole showed a marked pH-dependent solubility, 900μg mL−1 at pH 1.2 and less than 1.0μg mL−1 at pH 6.8. These results suggest that the absorption of albendazole is greatly influenced by gastric pH.

Effect of Gastric Digestion pH on Iron, Zinc, and Calcium Dialyzability from Preterm and Term Starting Infant Formulas

ABSTRACT: Iron, zinc, and calcium dialyzability from preterm and term starting infant formulas were determined after in vitro digestion, using special gastric conditions prevailing in preterm and newborn infants. Mineral dialyzability was studied using pH 2.0,3.5, and 4.5 for gastric digestion. The effect of gastric pH was more important on iron dialyzability (FeD) and zinc dialyzability (ZnD) than on calcium dialyzability (CaD). The effect on iron dialyzability was remarkable in fluid formulations with high digestibility: FeD was 18% to 20% when gastric digestion was made at pH 2, decreasing to 3% when made at pH 4.5. In most powder infant formulas with the lowest digestibility, FeD remained close to 10% despite variations in gastric digestion pH. Percent zinc dialyzability (ZnD%) steadily decreased when gastric digestion pH increased. At each pH, percent iron dialyzability (FeD%) and ZnD% from human milk were higher than those from infant formulas. Evaluation of mineral dialyzability from these infant formulas, using a gastric digestion pH prevailing in preterm and newborn infants, can provide valuable information on mineral availability.

Influence of cimetidine co-administration on the pharmacokinetics of acebutolol enantiomers and its metabolite diacetolol in a rat model: the effect of gastric pH on double-peak phenomena

Acebutolol (AC) is a chiral β-adrenergic receptor-blocking agent, which has been shown to be clinically effective in hypertension. The plasma concentration–time profiles of AC exhibit two peaks following oral administration of racemate for both R- and S-enantiomers. In the present study, the absorption of AC after a single dose was studied as a function of gastric pH in male Sprague–Dawley rats. Furthermore, the effect of cimetidine (CIM) on pharmacokinetic parameters of AC and its metabolite diacetolol (DC) was evaluated. CIM (50 mg kg −1) was administered via jugular vein 30 min prior to AC administration to elevate the intragastric pH. AC (50 mg kg −1) was administered orally by gavage and serial blood samples were collected before and for 8 h after AC administration. Plasma samples were assayed for AC and DC, pharmacokinetic parameters were estimated and compared with those of control. The concentration–time profiles and the pharmacokinetics of AC were unchanged after co-administration of CIM. The oral absorption of AC, as assessed by the area under the plasma concentration–time curve (AUC) and the amount of unchanged drug recovered in the urine were not affected by CIM. The amount of metabolite recovered in the urine and the rate of absorption, however, were significantly altered. These are unlikely to be of clinically importance as we have found that the extent of absorption was not changed. We, therefore, concluded that intragastric elevation of pH has no effect either on generation of multiple peaking or on pharmacokinetic parameters of AC.

Effect of gastric ph on plasma concentrations of tegaserod (HTF 919) and its major metabolite in healthy subjects

Effect of gastric ph on plasma concentrations of tegaserod (HTF 919) and its major metabolite in healthy subjects

Absolute Bioavailability of Halofantrine-Hcl: Effect of Ranitidine and Pentagastrin Treatment

AbstractThe first part of this study dealt with determination of the absolute oral bioavailability of halofantrine using six beagle dogs that were randomly assigned to two groups. The beagles in Group I had a single S mg/kg intravenous dose of halofantrine in the first period and a single 250 mg oral dose of halofantrine tablet in the second period with a washout period of six weeks. Those in Group II received the intravenous and oral doses in the opposite order.The effect of gastric pH on the absolute bioavailability was evaluated in the second part of the study. Six beagles received a single 5 mg/kg intravenous dose in the first period. They were randomly assigned to two groups six weeks after the intravenous dose. Those in Group I had 6 μg/kg pentagastrin intravenously 30 minutes before a single 230 mg oral dose of halofantrine tablet in the second period. They received 2.5 mg/kg intramuscular doses of ranitidine 10 and 2 hours before a single 250 mg oral dose of halofantrine tablet in the third period...

Effects of gastric pH on the activity of exogenous pentosanase and the effect of pentosanase supplementation of the diet on the performance of growing-finishing pigs

A series of experiments was conducted to determine the effect of pH on pentosanase activity and to monitor the effect of passage through the stomach of the pig on the ability of enzymes to degrade pentosans. In Experiment 1, pentosanase activity was determined in ten commercially available enzyme products at five pH levels (2.5, 3.5, 4.5, 5.5 and 6.5) using a discontinuous assay. Little activity was evident at pH 2.5, which was only slightly increased at pH 3.5. The highest activity occurred after the pH reached 4.5 or 5.5. Enzyme activity declined rapidly at pH 6.5. Experiment 2 was an in vitro trial designed to mimic the in vivo situation where enzymes would be exposed to a low pH in the stomach followed by a sudden rise in pH when the digesta entered the small intestine. Five enzyme preparations were incubated at three pH levels (2.5, 3.5 and 4.5) for 15, 30, 60 or 120 min. The pH level was then increased to pH 5.5 which was the optimum pH for activity determined in Experiment 1. All enzyme products were relatively stable when incubated at pH 4.5 and then returned to pH 5.5. Enzyme products treated at pH 3.5 only partially recovered activity when returned to pH 5.5 and all enzyme products exhibited a serious deterioration effect when incubated at pH 2.5 and returned to pH 5.5. Experiment 3 was designed to determine the amount of pentosanase activity leaving the stomach of the pig. Five castrates cannulated with a simple T-cannula located at the start of the duodenum were used in a 5 × 5 Latin Square design experiment. The diets consisted of a control diet and four diets supplemented with enzyme. The level of pentosanase activity in the duodenum was relatively stable and, across all products, 84% of initial activity was still present 240 min after feeding. Experiment 4 was conducted to evaluate the effectiveness of four enzyme sources in improving the performance of pigs fed rye-based diets. Performance of pigs fed rye was similar to that of pigs fed a barley-based diet ( P > 0.05). Supplementation with pentosanase generally ( P > 0.05) improved both growth and feed/gain ratios of pigs fed rye-based diets. The overall results of these experiments indicated that passage through the stomach of the pig did not inactivate pentosanase and provided a favorable indication that supplementation of rye-based diets with pentosanase may have the potential to improve pig performance.

Effect of gastric pH on urease-dependent colonization of gnotobiotic piglets by Helicobacter pylori

Thirty-seven gnotobiotic piglets from seven litters were infected with either Helicobacter pylori N6 or urease-negative H. pylori N6ureG::Km which contains an insertion in the ureG gene and produces inactive urease. To produce achlorhydria, piglets were treated throughout the experiment with omeprazole (5 mg intravenously every 12 h) and ranitidine (75 mg orally every 6 h). Treatment resulted in elevation of gastric pH to 7.0 +/- 1.1 throughout the experiment. Control piglets were not treated and remained normochlorhydric. Strain N6 colonized well in both normal and achlorhydric piglets. All 10 piglets were colonized, and colonization ranged from 4.4 +/- 1.5 log10 CFU/g of gastric mucosa in normochlorhydric piglets sacrificed after 2 days to 6.9 +/- 0.5 log10 CFU/g in normochlorhydric piglets sacrificed after 5 days. Strain N6ureG::Km did not colonize any of seven normochlorhydric piglets and was recovered only in low numbers (< 100 CFU/g) from four of nine achlorhydric piglets. In the second experiment, piglets were coinoculated with both strains N6 and N6ureG::Km. Coinoculation did not affect colonization by urease-positive N6. Urease-deficient N6ureG::Km was unable to colonize even in the presence of urease-positive bacteria. These results confirm that urease enzymatic activity (and not urease protein) is essential for colonization, that this effect is independent of diffusible products of urea metabolism, and that gastric pH protection is not a major role of urease in promoting colonization by H. pylori.

The effect of gastric pH on the absorption of controlled-release theophylline dosage forms in humans.

The bioavailability of three marketed controlled-release dosage forms and a reference solution of theophylline was studied in eight subjects with normal gastric fluid acidity and seven subjects who were achlorhydric. Gastric pH was monitored with a Heidelberg capsule. One of the controlled-release dosage forms dissolved more rapidly in vitro when exposed to acid conditions, one dissolved more rapidly in pH 7.5 media, and the third dissolved at a rate independent of pH. Using a crossover design, each subject received each dosage form twice. Blood was sampled for up to 47 hr after each dose, and serum was assayed for theophylline by HPLC. The product which dissolved more rapidly under acid conditions in vitro exhibited a 3 hr longer Tmax in the achlorhydrics compared to the normal subjects. The product which dissolved more rapidly in the pH 7.5 media exhibited a relatively higher AUC(0-infinity) in the achlorhydric subjects than in normal subjects after the AUC data were normalized for clearance differences between the two subject groups. The in vivo bioavailability of these dosage forms could be related to the in vitro dissolution characteristics for some parameters. However, with the exception of the mean Tmax values, the mean bioavailability parameters differed by less than 20% between the two subjects groups.

Effect of Gastric pH on the Nosocomial Pneumonia in Long - term Intubated Patients

Effect of Gastric pH on the Nosocomial Pneumonia in Long - term Intubated Patients

Gastric nitrate reduction and nitrosation of trimethylurea in swine treated with pentagastrin or cimetidine

Swine were treated with cimetidine in order to quantify the reduction of nitrate to nitrite and the gastric formation of N-nitrosotrimethylurea (NTMU) under conditions similar to those in the achlorhydric human stomach. Gastric-fistulated swine were instilled with 6.0 mmol of nitrate in 50 ml water, after which gastric nitrate, nitrite and pH were monitored. Trimethylurea, 250 mumol in 50 ml water, was instilled via the fistula 10 min following the peak gastric nitrite concentration. Similar experiments were conducted with pentagastrin-stimulated animals, in order to quantitate the effect of gastric pH and microflora on the presence of nitrate, nitrite and NTMU formation. The stomachs of cimetidine-treated pigs (elevated pH) were colonized by nitrate reductase organisms to levels of 10(4)-10(7)/ml gastric fluid. Gastric nitrite concentration in cimetidine-treated animals reached a maximum of 370-2085 microM, 60 min following the nitrate dose. Trimethylurea was only marginally nitrosated (less than 0.1 mumol/l gastric fluid) in cimetidine- or pentagastrin-stimulated animals. The low yield of NTMU at elevated pH, in the presence of substantial nitrite, suggests that the nitrate-reducing bacteria present in the porcine stomach did not catalyze trimethylurea nitrosation in vivo.

Survival and virulence of copper- and chlorine-stressed Yersinia enterocolitica in experimentally infected mice.

The effect of gastric pH on the viability and virulence of Yersinia enterocolitica O:8 after exposure to sublethal concentrations of copper and chlorine was determined in mice. Viability and injury were assessed with a nonselective TLY agar (tryptic soy broth containing lactose, yeast extract, and agar) and two selective media, TLYD agar (TLY agar plus sodium deoxycholate) and CIN agar (cefsulodin-Irgasan-novobiocin agar). Both copper and chlorine caused injury which was manifested by the inability of the cells to grow on selective media. CIN agar was more restrictive to the growth of injured cells than TLYD agar. Injury of the exposed cells was further enhanced in the gastric environment of mice. Besides injury, the low gastric pH caused extensive loss of viability in copper-exposed cells. Lethality in the chlorine-exposed cells was less extensive, and a portion of the inoculum (5.2 X 10(5) of 1 X 10(7) inoculated cells) reached the small intestine 5 min postinoculation. No adverse effect on the injured cells was apparent in the small intestine, and a substantial revival (approximately 70%) of the injury occurred in 3 to 4 h after intraluminal inoculation. The virulence of chlorine-stressed Y. enterocolitica in orally inoculated mice was similar to that of the control culture, but copper-stressed cells showed reduced virulence. Virulence was partly restored by oral administration of sodium bicarbonate before the inoculation of copper-exposed cells. Neutralization of gastric acidity had no effect on the virulence of the control or chlorine-stressed cells. The results of this study indicate that the extensive injury caused by the low gastric pH does not affect the virulence potential of chlorine-exposed cells. However, extensive cell death in the mouse stomach is responsible for the reduced virulence of the copper-stressed bacteria.