A Semi-mechanistic Gastric Emptying Model for the Population Pharmacokinetic Analysis of Orally Administered Acetaminophen in Critically Ill Patients

Purpose  

To develop a semi-mechanistic population pharmacokinetic model based on gastric emptying function for acetaminophen plasma concentration in critically ill patients tolerant and intolerant to enteral nutrition before and after prokinetic therapy.     

Gastric Emptying of Pellets under Fasting Conditions: A Mathematical Model

Purpose  To develop a mathematical model that would adequately describe human gastric emptying of pellets under fasting conditions of healthy subjects. Methods  Scintigraphic profiles representing the gastric emptying of pellets were obtained from the literature. Altogether 19 individual and three mean scintigraphic profiles were collected. Three mathematical models namely; the lag-time exponential (two parameters), the Weibull (two parameters), and the double Weibull (five parameters) model were proposed and fitted to the gastric emptying profiles. Results  Different patterns of gastric emptying (immediate and rapid, delayed but rapid, delayed and slow, and interruptive emptying) were observed, with the emptying time varied from approximately 15 min to more than 3 h. The best model for fitting to the individual profiles was the double Weibull model. This model also provided an insight into the mechanism of interruptive emptying of pellets, observed for some patients. In addition, mean gastric emptying of pellets was calculated using the Weibull model. Conclusions  Mean gastric emptying of pellets was adequately described by the Weibull model (η = 61.9 min, β = 0.895), which could be applied in the design of in vitro dissolution experiments for pellet formulations with pH dependent dissolution.     

Influence of the pharmacological modification of gastric emptying on lactose digestion and gastrointestinal symptoms

Background:

In lactose maldigesters the ingestion of food which retards gastric emptying improves tolerance to lactose.

Aim:

To study the effects of the pharmacological modification of gastric emptying on the speed of development of lactose-induced symptoms.

Methods:

After an overnight fast, 18 lactose maldigesters were given, in a randomized double-blind study design at 1-week intervals, either propantheline (as bromide 15 mg), metoclopramide (as hydrochloride 10 mg) or placebo, in identical capsules, 60 min before ingesting 50 g lactose coloured with 1 g carmine dye (to measure gastrointestinal transit time). Gastrointestinal symptoms, urinary galactose excretion, and breath hydrogen and blood glucose concentrations were recorded.

Results:

The propantheline-induced prolongation of gastric emptying improved tolerance to lactose, as measured by reduced area under the gastrointestinal symptom score curve 0–12 h, compared to placebo (by 26%) (P < 0.05) or metoclopramide (by 30%) (P < 0.05). The total hydrogen excretion AUC (180 min follow-up) increased by 15% after metoclopra- mide as compared with placebo (P = 0.18). Propantheline decreased this variable by 15% from placebo (P = 0.17). No significant differences in blood glucose, urinary galactose or gastrointestinal transit time were found.

Conclusions:

In an oral lactose tolerance test, delaying gastric emptying with propantheline improved tolerance in lactose maldigesters, as measured by diminished gastrointestinal symptoms and reduced breath hydrogen concentration.

     

功能性消化不良病人胃排空功能改变的危险因素

目的 :研究功能性消化不良病人胃排空功能的异常与症状之间的关系及西沙比利疗效。方法 :对 36例功能性消化不良病人 4种症状进行分级 ,并行胃排空检查 ,分别与健康人对照组 12例比较 ,并与西沙比利 5mg ,po ,tid治疗后自身对照比较。结果 :半排时间固体实验组治疗前为 5 9min±s 10min ,健康人对照组为 5 0min± 11min(P <0 .0 5 ) ,治疗后为 4 9min± 9min(P <0 .0 5 ) ;液体半排时间分别为 13min± 4min ,15min± 6min (P >0 .0 5 ) ,治疗后为 13min± 3min与治疗前比较P >0 .0 5。腹胀、腹痛、恶心、呕吐与固体胃排空延迟的回归系数分别为 0 .381,0 .5 43,0 .178,0 .4 63。结论 :功能性消化不良病人固体胃排空延迟 ,且可被西沙比利纠正 ,腹胀、腹痛、呕吐是固体胃排空延迟的危险因素     

Pharmacokinetics of Paracetamol in Göttingen Minipigs: In Vivo Studies and Modeling to Elucidate Physiological Determinants of Absorption

Purpose

Onset and rate of gastric emptying are important determinants of drug absorption after oral dosing. Therefore, robust estimates of these parameters are needed in physiologically based absorption models to predict reliably plasma concentration time profiles. For human and some other laboratory animals, reasonable parameterization of gastric emptying has been established. However gastric emptying is less well characterized in minipigs, a large animal model rapidly gaining importance in pharmaceutical research.

Methods

A pharmacokinetic crossover study using different dosage forms of paracetamol (intravenous and oral solution, capsule and tablet) was conducted in four male and four female Göttingen minipigs after an overnight fast. Deconvolution analysis was performed to determine the absorption kinetics. Estimated lag times and first order gastric emptying parameters were incorporated in a previously published PBPK model of the minipig and simulations verified. Postmortem assessments of minipig stomachs were made after different fasting protocols.

Results

Fraction of dose absorbed vs. time profiles showed high interindividual variability, comparable to human fed state absorption. Mean gastric transit times were determined to be 0.63 h, 1.36 h, and 0.73 h for solution, capsules, and tablets, respectively. Postmortem assessment confirmed that minipig stomachs were not empty after an overnight fast.

Conclusions

Gastric transit times in overnight fasted minipigs are longer than those observed in humans. This is most likely caused by delayed and incomplete food emptying and further work is needed to develop feasible and effective fasting protocols for minipigs.     

Measurement of Drug Concentration in the Stomach After Intragastric Administration of Drug Solution to Healthy Volunteers: Analysis of Intragastric Fluid Dynamics and Drug Absorption

Purpose

To evaluate the time-profile of intragastric fluid volume in humans after intragastric administration of drug solution.

Methods

Eight healthy volunteers were intragastrically administered 150 mL of drug solution containing atenolol (non-absorbable marker) and salicylic acid, then, aliquots of gastric fluid (ca. 2 mL) were sampled for 2 h through the catheter. Rate constants for secretion and emptying of the fluid were obtained by fitting the time-course of atenolol concentration to the simple gastric fluid transit model. Absorption of salicylic acid from the stomach was estimated by comparing its gastric concentration with that of atenolol.

Results

Kinetic analysis of atenolol concentration in the stomach indicated a rapid emptying of the fluid with an average half-life of 4.2 min. Steady-state intragastric fluid volume in 8 volunteers was estimated as 4–133 mL with an average of 42 mL. Intragastric concentration (normalized by dose) of salicylic acid was always lower than that of atenolol, showing approximately 40% of salicylic acid was absorbed from the stomach before emptying to the intestine.

Conclusions

This study provided valuable information on intragastric fluid dynamics and gastric drug absorption in humans to establish a better in vitro-in vivo correlation in oral drug absorption.     

Delta-9-tetrahydrocannabinol delays the gastric emptying of solid food in humans: a double-blind, randomized study

Background:

Delta-9-tetrahydrocannabinol (THC), the active constituent of marijuana, is an effective agent in the prevention of chemotherapy-induced nausea and vomiting.

Aim:

To determine the effect of THC on gastric emptying of a radiolabelled solid food in humans.

Methods:

Thirteen healthy volunteers underwent gastric emptying studies after receiving THC and placebo in a randomized double-blind fashion on 2 separate days. THC, at a dose of 10 mg/m² of body surface area, or placebo were administered.

Results:

Gastric emptying after THC was slower than placebo in all subjects. Mean percentage of isotope remaining in the stomach was significantly greater than after placebo from 30 min (85.5 ± 4.3% vs. 94.2 ± 1.4% placebo and THC, respectively, P < 0.05) to 120 min (45.6 ± 7.2% vs. 73.9 ± 7.1% placebo and THC, respectively, P < 0.001) after the test meal. No correlation was found between plasma THC levels and the delay in gastric emptying.

Conclusions:

THC at a dose used for preventing chemotherapy-induced nausea and vomiting significantly delays gastric emptying of solid food in humans. Therefore, the anti-emetic property of THC may be mediated through the central nervous system.

     

Review article: the role of gastric motility in the control of food intake

Aliment Pharmacol Ther 2011; 33: 880–894

Summary

Background From a classical point of view, gastric motility acts to clear the stomach between meals, whereas postprandial motility acts to provide a reservoir for food, mixing and grinding the food and to assure a controlled flow of food to the intestines. Aim To summarise findings that support the role of gastric motility as a central mediator of hunger, satiation and satiety. Methods A literature review using the search terms ‘satiety’, ‘satiation’ and ‘food intake’ was combined with specific terms corresponding to the sequence of events during and after food intake. Results During food intake, when gastric emptying of especially solids is limited, gastric distension and gastric accommodation play an important function in the regulation of satiation. After food intake, when the stomach gradually empties, the role of gastric distension in the determination of appetite decreases and the focus will shift to gastric emptying and intestinal exposure of the nutrients. Finally, we have discussed the role of the empty stomach and the migrating motor complex in the regulation of hunger signals. Conclusions Our findings indicate that gastric motility is a key mediator of hunger, satiation and satiety. More specifically, gastric accommodation and gastric emptying play important roles in the regulation of gastric (dis)tension and intestinal exposure of nutrients and hence control satiation and satiety. Correlations between gastric accommodation, gastric emptying and body weight indicate that gastric motility can also play a role in the long‐term regulation of body weight.     

The mGluR2/3 agonist LY379268 reverses post-weaning social isolation-induced recognition memory deficits in the rat

Rationale  

Current antipsychotics are ineffective at treating the negative and cognitive symptoms of schizophrenia, so there is a substantial need to develop more effective therapeutics for this debilitating disorder. The type II metabotropic glutamate receptor (mGluR2/3) is a novel, potential therapeutic target requiring evaluation in appropriate preclinical models of schizophrenia.     

Beta-casein Nanoparticles as an Oral Delivery System for Chemotherapeutic Drugs: Impact of Drug Structure and Properties on Co-assembly

Purpose  

To develop a novel oral drug delivery system comprising a hydrophobic chemotherapeutic drug entrapped within beta casein (β–CN), a major milk protein, which self-associates into micelles in aqueous solutions. The efficient gastric digestibility of β–CN suggests possible targeting to gastric cancers.     

Effect of the motilin agonist KC 11458 on gastric emptying in diabetic gastroparesis

BACKGROUND: KC 11458, a motilin agonist without antibiotic properties, accelerates gastric emptying in animals and healthy humans. AIM: To evaluate the acute effects of KC 11458 on gastric emptying in diabetic gastroparesis. METHODS: Twenty-nine patients (6 type 1 and 23 type 2) with gastroparesis underwent assessments of: (i) gastric emptying of a solid/liquid meal using scintigraphy, (ii) glycaemic control (blood glucose at 0, 30, 60, 90 and 120 min during the gastric emptying measurement) and (iii) upper gastrointestinal and 'meal-related' symptoms (questionnaire), at baseline and after treatment with KC 11458 in a dose of 8 mg t.d.s., or placebo for 8 days. RESULTS: KC 11458 had no statistically significant or clinically relevant effect on gastric emptying of either the solid intragastric retention at 100 min (T100) (P = 0.87) or liquid 50% emptying time (T50) (P = 0.17) components of the meal. KC 11458 slightly worsened (P = 0.04) upper gastrointestinal symptoms when compared with placebo. The magnitude of the change in solid gastric emptying correlated with the change in the blood glucose concentration (r = 0.49; P < 0.05). CONCLUSIONS: KC 11458, in a dose of 8 mg t.d.s. for 8 days, does not accelerate gastric emptying in patients with diabetic gastroparesis. The absence of efficacy may relate to an effect of hyperglycaemia.     

Central activation of the cholinergic anti-inflammatory pathway reduces surgical inflammation in experimental post-operative ileus

BACKGROUND AND PURPOSE

Electrical stimulation of the vagus nerve reduces intestinal inflammation following mechanical handling, thereby shortening post-operative ileus in mice. Previous studies in a sepsis model showed that this cholinergic anti-inflammatory pathway can be activated pharmacologically by central administration of semapimod, an inhibitor of p38 mitogen-activated protein kinase. We therefore evaluated the effect of intracerebroventricular (i.c.v.) semapimod on intestinal inflammation and post-operative ileus in mice.

EXPERIMENTAL APPROACH

Mice underwent a laparotomy or intestinal manipulation 1 h after i.c.v. pre-treatment with semapimod (1 µg·kg⁻¹) or saline. Drugs were administered through a cannula placed in the left lateral ventricle 1 week prior to experimentation. Twenty-four hours after surgery, gastric emptying was measured using scintigraphy, and the degree of intestinal inflammation was assessed. Finally, activation of brain regions was assessed using quantitative immunohistochemistry for c-fos.

KEY RESULTS

Intestinal manipulation induced inflammation of the manipulated intestine and significantly delayed gastric emptying, 24 h after surgery in saline-treated animals. Semapimod significantly reduced this inflammation and improved gastric emptying. Vagotomy enhanced the inflammatory response induced by intestinal manipulation and abolished the anti-inflammatory effect of semapimod. Semapimod but not saline induced a significant increase in c-fos expression in the paraventricular nucleus, the nucleus of the solitary tract and the dorsal motor nucleus of the vagus nerve.

CONCLUSIONS AND IMPLICATIONS

Our findings show that i.c.v. semapimod reduces manipulation-induced intestinal inflammation and prevented post-operative ileus. This anti-inflammatory effect depends on central activation of the vagus nerve.     

Review article: the impact of bariatric surgery on gastrointestinal motility

Aliment Pharmacol Ther 2011; 34: 825–831

Summary

Background Obesity is a major medical problem worldwide. Different treatment modalities have emerged to treat obese patients, but the best long‐term results are achieved with bariatric surgery. Currently, the interventions most commonly performed are laparoscopic adjustable gastric banding (LAGB), Roux‐en‐Y‐ gastric bypass (RYGB) and sleeve gastrectomy. Aim To review the gastrointestinal motor complications associated with each of these types of bariatric interventions and the clinical implications of such complications. Methods Search of medical database (PubMed) on English‐language articles from January 1996 to March 2011. The search terms used were laparoscopic adjustable gastric banding (LAGB), sleeve gastrectomy (LSG), roux‐en‐Y‐gastric bypass (RYGB), using the AND operator with the terms: complications, motility, GERD, reflux, gastric emptying, esophagitis, dysphagia. Results Of the three bariatric interventions reviewed, LAGB was the most studied. Most studies reported short follow‐up, of ≤1 year. Oesophageal motor dysfunction is the most common motility complication following the bariatric interventions that were reviewed and is mainly observed after LAGB. Some data suggest that oesophageal motor function testing predicts development of post‐operative symptoms and oesophageal dilation. RYGB offers protection from gastro‐oesophageal reflux. Sleeve gastrectomy was the least studied and was associated with an acceleration of gastric emptying. Conclusions The effects of these interventions on GI motility should be considered when selecting patients for bariatric surgery. There is scant information regarding the overall effect of sleeve gastrectomy on gastro‐oesophageal reflux patterns and oesophageal motility.     

Gastric emptying and absorption of acetylsalicylic acid administered as enteric-coated micro-granules

Summary Enteric-coated and uncoated microgranules of acetylsalicylic acid (ASA), labelled with⁵¹Cr, were administered orally to six healthy male volunteers in a cross-over study. Gastric emptying was studied using a profile scanning radiation technique. Absorption of ASA was followed by measuring the plasma concentration of salicylate. Gastric emptying both of uncoated and enteric-coated granules varied considerably between individuals, but in most cases was gradual and extended over a period of several hours. The median time until 50% and 90% were emptied from the stomach was 1 and 3–3.5 h, respectively, for both the uncoated and enteric-coated granules. The absorption of ASA from the uncoated granules occurred in parallel with the gastric emptying. However, with the enteric-coated granules, absorption was delayed for about 3 h after gastric emptying. It was concluded that the slow absorption of ASA from enteric-coated granules could be explained partly by gradual gastric emptying and partly by slow dissolution of the ASA granules in the intestine.     

Pathophysiology and management of diabetic gastropathy: a guide for endocrinologists

Delayed gastric emptying is frequently observed in patients with long-standing type 1 and type 2 diabetes mellitus, and potentially impacts on upper gastrointestinal symptoms, glycaemic control, nutrition and oral drug absorption. The pathogenesis remains unclear and management strategies are currently suboptimal. Therapeutic strategies focus on accelerating gastric emptying, controlling symptoms and improving glycaemic control. The potential adverse effects of hyperglycaemia on gastric emptying and upper gut symptoms indicate the importance of normalising blood glucose if possible. Nutritional and psychological supports are also important, but often neglected. A number of recent pharmacological and non-pharmacological therapies show promise, including gastric electrical stimulation. As with all chronic illnesses, a multidisciplinary approach to management is recommended, but there are few data regarding long-term outcomes.     

Effects of antipsychotic treatment on psychopathology and motor symptoms. A placebo-controlled study in healthy volunteers

Rationale  

There is increased interest in elucidating the range of symptoms of schizophrenia and their response to treatment with medications. Particularly negative and cognitive symptoms are often resistant to the therapy with currently available antipsychotics. There are even similarities between negative symptoms in psychosis and the side effects of antidopaminergic antipsychotic drugs.     

The rate of gastric emptying determines the timing but not the extent of oral tacrolimus absorption: simultaneous measurement of drug exposure and gastric emptying by carbon-14-octanoic acid breath test in stable renal allograft recipients.

Tacrolimus is characterized by a highly variable oral bioavailability and narrow therapeutic window. Tacrolimus absorption from the gastrointestinal tract is to a large extent determined by the genotypic, phenotypic, and functional expression of P-glycoprotein and CYP3A in the gut wall and liver. It is disputed whether the gastric emptying rate per se is important for determining oral bioavailability of tacrolimus and whether delayed gastric emptying is clinically relevant for therapeutic drug dosing. We conducted a pharmacokinetic study in 50 renal recipients, measuring simultaneously the rate of gastric emptying using a carbon-14-octanoic acid breath test and quantifying drug exposure by area under the concentration-time curve sampling. Gastric half emptying time (t1/2) significantly correlated with time to reach maximum blood tacrolimus (tmax) concentration (r2 = 0.30; p < 0.0001), whereas the gastric emptying coefficient, reflecting the overall gastric emptying rate, showed a weak inverse correlation with tmax (r2 = 0.14; p = 0.007). The time-dependent rate of gastric emptying strongly correlated with the simultaneously measured blood tacrolimus concentration over the first 4 h after oral drug administration (r2 = 0.96; p < 0.0001). Comparison between patients with and without delayed gastric emptying confirmed that maximum blood tacrolimus concentration was reached significantly more slowly in the former group (tmax, 2 +/- 1 h versus 1.48 +/- 0.68 h; p = 0.04), whereas the extent of tacrolimus absorption was not different. Despite a strong association between gastric emptying rate and the timing of tacrolimus absorption from the gut in stable recipients, gastric emptying rate does not affect the total extent of drug absorption and is not responsible for significant alterations in drug exposure, even in situations of delayed gastric emptying.     

Effects of fedotozine on gastric emptying and upper gastrointestinal symptoms in diabetic gastroparesis

BACKGROUND: Delayed gastric emptying and upper gastrointestinal symptoms occur frequently in patients with diabetes mellitus. AIM: To evaluate the effects of fedotozine on gastric emptying and gastrointestinal symptoms in diabetic gastroparesis. METHODS: Thirty-one diabetic patients (20 type 1, 11 type 2) with gastroparesis were randomized to receive fedotozine (30 mg as the tartrate) or placebo t.d.s. Measurements of gastric emptying (100 g ground beef labelled with 20 MBq 99mTc-sulphur colloid chicken liver and 150 mL 10% dextrose labelled with 10 MBq 113mIn-DTPA) and gastrointestinal symptoms were performed before and after 12-16 days of treatment. Data are the mean +/- s.d. RESULTS: Of the 31 patients enrolled, two were excluded from analysis. Data from the remaining 29 patients (18 type 1, 11 type 2; 22 female, seven male), aged 42.7 +/- 11.1 years (of whom 14 were randomized to fedotozine and 15 to placebo), were analysed. Fedotozine had no effect on either gastric emptying (solid retention at 100 min; fedotozine: baseline, 84 +/- 15%; treatment, 73 +/- 23% vs. placebo: baseline, 83 +/- 10%; treatment, 70 +/- 20%) or liquid 50% emptying time (fedotozine: baseline, 59 +/- 32 min; treatment, 58 +/- 38 min vs. placebo: baseline, 44 +/- 9 min; treatment, 43 +/- 21 min) or gastrointestinal symptoms (fedotozine: baseline, 4.4 +/- 2.9; treatment, 4.1 +/- 3.9 vs. placebo: baseline, 4.9 +/- 4.2; treatment, 4.8 +/- 3.9). CONCLUSIONS: Fedotozine has no effect on gastric emptying in patients with diabetic gastroparesis.     

In vitro and in vivo pharmacological role of TLQP-21, a VGF-derived peptide,in the regulation of rat gastric motor functions

Background and purpose:

Vgf gene expression has been detected in various endocrine and neuronal cells in the gastrointestinal tract. In this study we investigated the pharmacological activity of different VGF-derived peptides. Among these, TLQP-21, corresponding to the 556–576 fragment of the protein was the unique active peptide, and its pharmacological profile was further studied.

Experimental approach:

The effects of TLQP-21 were examined in vitro by smooth muscle contraction in isolated preparations from the rat gastrointestinal tract and, in vivo, by assessing gastric emptying in rats. Rat stomach tissues were also processed for immunohistochemical and biochemical characterization.

Key results:

In rat longitudinal forestomach strips, TLQP-21 (100 nmol·L⁻¹–10 µmol·L⁻¹) concentration-dependently induced muscle contraction (in female rats, EC₅₀ = 0.47 µmol·L⁻¹, E_max: 85.7 ± 7.9 and in male rats, 0.87 µmol·L⁻¹, E_max: 33.4 ± 5.3; n = 8), by release of prostaglandin (PG)E₂ and PGF_2a from the mucosal layer. This effect was significantly antagonized by indomethacin and selective inhibitors of either cyclooxygenase-1 (S560) or cyclooxygenase-2 (NS398). Immunostaining and biochemical studies confirmed the presence of VGF in the gastric neuronal cells. TLQP-21, injected i.c.v. (2–32 nmol per rat), significantly decreased gastric emptying by about 40%. This effect was significantly (P < 0.05) blocked by i.c.v. injection of indomethacin, suggesting that, also in vivo, this peptide acts in the brain stimulating PG release.

Conclusions and implications:

The present results demonstrate that this VGF-derived peptide plays a central and local role in the regulation of rat gastric motor functions.     

Biorelevant Media to Simulate Fluids in the Ascending Colon of Humans and Their Usefulness in Predicting Intracolonic Drug Solubility

Purpose  

To develop media simulating human colonic fluids (HCFs), to evaluate their use in predicting intracolonic solubility of ketoconazole, danazol and felodipine and to compare solubilities in HCFs with previously determined solubilities in gastric (HGFs) and small intestinal (HIFs) fluids.