Jari Rubbens

The dynamic gastric environment and its impact on drug and formulation behaviour

Before being absorbed in the small intestine and/or colon, orally administered drugs inevitably need to pass through the stomach. Hence, it seems reasonable that the residence of a dosage form in the gastric environment, however brief it may be, may influence drug disposition further down the gastrointestinal tract and may potentially impact systemic exposure to a drug of interest. However, research efforts in the past mainly focused on drug disposition at the level of the intestine, i.e. the main site of absorption, hereby disregarding or oversimplifying the stomachs contribution to gastrointestinal drug disposition. In the first part of this review, the complexity of the stomach with regard to anatomy, physiology and gastric fluid composition is emphasized. Between-population differences in gastric functioning and physicochemical characteristics of gastric fluids are discussed. The second part of this review focuses on several of the processes to which a dosage form can be exposed during its passage through the stomach and the implications for gastrointestinal drug behaviour and systemic drug disposition. Finally, the influence of real-life dosing conditions on drug disposition is discussed in the context of the stomach.

Ethanol concentrations in the human gastrointestinal tract after intake of alcoholic beverages

INTRODUCTION The goal of this study was to monitor gastric and duodenal ethanol concentrations arising from the consumption of commonly used alcoholic beverages. MATERIALS AND METHODS In a cross-over study, five fasting volunteers were asked to drink two standard consumptions of commercially available alcoholic beverages, including beer (Stella Artois®, 500 mL, 5.2% ethanol), wine (Blanc du Blanc®, 200 mL, 11% ethanol) and whisky (Gallantry Whisky®, 80 mL, 40% ethanol). The volunteers finished drinking beer within 10 min and wine or whisky within 5 min. Ethanol concentrations in gastric and duodenal fluids, aspirated as a function of time, were analyzed by headspace gas chromatography. RESULTS In all three conditions, the average gastric profile shows a maximum ethanol concentration (Cmax) at 7 min, while the mean duodenal profiles have a Tmax at 20, 7 and 12 min for beer, wine and whisky, respectively. The median gastric ethanol Cmax (min-max) for the beer, wine and whisky conditions amounts to 4.1% (3.1-4.1), 4.1% (2.6-7.3) and 11.4% (6.3-21.1), respectively. The mean duodenal profiles follow the same pattern as their corresponding gastric profiles, albeit with lower percentages of ethanol. Median duodenal ethanol Cmax (min-max) for beer, wine and whisky are 1.97% (0.89-4.3), 2.39% (2.02-5.63) and 5.94% (3.55-17.71), respectively. Intraluminal ethanol concentrations appear to decline relatively rapidly in fasting conditions: both stomach and duodenum contained less than 0.05% of ethanol after 120 min. CONCLUSIONS This in vivo study is the first to present intraluminal ethanol concentrations in man after the intake of alcoholic beverages. Relatively low and fast declining gastric ethanol concentrations were observed, contrasting with the current Food and Drug Administration guidelines for the in vitro testing of formulations with respect to ethanol resistance. The presented gastric and duodenal ethanol concentrations and their variation may serve as reference data to design relevant models for predicting (i) ethanol resistance of drug formulations and (ii) ethanol effects on drug solubility and permeability.

Gastrointestinal dissolution, supersaturation and precipitation of the weak base indinavir in healthy volunteers.

This study investigated the impact of relevant gastrointestinal conditions on the intraluminal dissolution, supersaturation and precipitation behavior of the weakly basic drug indinavir. The influence of (i) concomitant PPI intake and (ii) the nutritional state on the gastrointestinal behavior of indinavir was assessed in order to identify the underlying mechanisms responsible for previously reported interactions. Five healthy volunteers were recruited into a crossover study containing the following arms: fasted state, fed state and fasted state with concomitant proton pump inhibitor (PPI) use. In each condition, one Crixivan® capsule (400mg indinavir) was orally administered with 240mL of water. Gastric and duodenal fluids, aspirated as a function of time, were monitored for total and dissolved indinavir concentrations on a UPLC-MS/MS system. Indinavirs thermodynamic solubility was determined in individual aspirates to evaluate supersaturation. The bioaccessible fraction of indinavir in aspirated duodenal fluids was determined in an ex vivo permeation experiment through an artificial membrane. A nearly complete dissolution of indinavir in the fasted stomach was observed (90±3%). Regardless of dosing conditions, less indinavir was in solution in the duodenum compared to the stomach. Duodenal supersaturation was observed in all three testing conditions. The highest degrees of duodenal supersaturation (6.5±5.9) were observed in the fasted state. Concomitant PPI use resulted in an increased gastric pH and a smaller fraction of indinavir being dissolved (58±24%), eventually resulting in lower intestinal concentrations. In fed state conditions, drug release from the capsule was delayed and more gradually, although a similar fraction of the intragastric indinavir dissolved compared to the fasted state (83±12%). Indinavir was still present in the lumen of the duodenum three hours after oral administration, although it already reached 70% (on average) of the fasted state concentrations (expressed as AUC0-3h). Based on a 2-h permeation experiment, the bioaccessible fraction of indinavir was 2.6-fold lower in a fed state sample compared to a fasted state sample. Our data indicate that the reported reduction in indinavirs bioavailability after concomitant PPI administration is caused by an elevated gastric pH resulting in less indinavir in solution in the stomach and, subsequently, reduced duodenal concentrations. In fed state conditions, however, intestinal micellar entrapment of indinavir appeared to cause the reported reduced bioavailability, regardless of duodenal concentrations.

Evaluation of real‐life dosing of oral medicines with respect to fluid and food intake in a Dutch‐speaking population

Oral drug administration is the most preferred route of drug administration. For some specific classes of drugs, recommendations regarding the intake of the drug product are provided by and approved in the summary of product characteristics (SmPC) after testing the oral drug product in clinical trials under strict and predefined conditions. The aim of this study was to investigate how certain classes of medicines are taken in a “real‐life” setting in terms of concomitant fluid and food intake by a Dutch‐speaking population in Flanders (Belgium). The outcome of this study was comprehensively discussed with literature data to evaluate the positive or negative consequences of their drug intake in daily life.

Intestinal disposition of quercetin and its phase-II metabolites after oral administration in healthy volunteers

Quercetin is one of the main dietary flavonoids and undergoes a substantial intestinal phase‐II metabolism. Quercetin conjugates have been detected in plasma and in urine, but their presence in the small intestine has not been assessed. This study aimed to investigate the intestinal metabolism and metabolite excretion of quercetin by the human small intestinal wall after oral dosing.

Exploring gastric drug absorption in fasted and fed state rats

ABSTRACT The small intestine is generally considered the major site of absorption after oral drug administration. Absorption from the stomach is often disregarded, though passive diffusion across the gastric mucosal barrier is theoretically possible. In this study, an in situ gastric bolus administration model was used to study the gastric absorption of pharmaceutical compounds in fasted and fed state rats. Three drugs [paracetamol (neutral), diclofenac (acidic) and posaconazole (basic)] were administered directly into the stomach as solution (paracetamol and diclofenac) or suspension (posaconazole). Transfer to the intestine was blocked by ligating the pylorus; as a reference, non‐ligated conditions were used. Blood samples were collected and gastric absorption was assessed by the appearance of compounds in the systemic circulation. Paracetamol and diclofenac were readily absorbed from the fasted and fed state rat stomach. For paracetamol, the relative contribution of gastric absorption was higher in the fed state compared to the fasted state. Posaconazole absorption was negligible. Since the ability of the stomach to absorb pharmaceutical compounds was clearly confirmed, the present study warrants further research to quantify the contribution of gastric absorption to total gastrointestinal drug absorption.

Gastric and Duodenal Ethanol Concentrations after Intake of Alcoholic Beverages in Postprandial Conditions

This study determined intraluminal ethanol concentrations (stomach and duodenum) in fed healthy volunteers after the consumption of common alcoholic beverages (beer, wine, and whisky). The results of this study were compared with a previous study in fasted volunteers. Five healthy volunteers were recruited in a crossover study. The fed state was simulated by ingestion of 250 mL of Nutridrink Compact Neutral. Volunteers subsequently consumed two standard units of beer (Stella Artois, 500 mL, 5.2% ethanol), wine (Blanc du Blanc, 200 mL, 11% ethanol), or whisky (Gallantry Whisky, 80 mL, 40% ethanol). Gastric and duodenal fluids were aspirated through two catheters over time and analyzed for ethanol content by head space gas chromatography. The capability of ethanol to permeate gastric and duodenal rat mucosa was examined in an Ussing chambers setup. A similar average gastric Cmax was observed in the beer and the wine conditions: 3.3% and 3.7% ethanol, respectively. The gastric Cmax in the whisky condition amounted to 8.5% ethanol. Lower ethanol concentrations were observed in the duodenum compared to the stomach. The duodenal Cmax was similar in all three conditions: 1.3%, 1.2%, and 1.6% ethanol for beer, wine, and whisky, respectively. Compared to the fasted state (reported in a previous study), higher gastric ethanol concentrations were observed during a longer time period. In the beer and wine conditions, similar concentrations were observed in the intestine regardless of the prandial state. After intake of whisky, however, the ethanol concentration was lower in the fed intestine. Alcohol was observed to permeate both gastric and duodenal rat mucosa. Higher intragastric ethanol concentrations were maintained for a longer period of time in fed compared to fasted state conditions. However, the observed concentration profiles were not in line with current FDA guidelines for alcohol resistance testing of formulations, stating that in vitro tests should investigate the impact of up to 40% ethanol for 2 h. The presented intraluminal ethanol concentrations may serve as reference data for the further development of relevant in vitro models to assess ethanol effects on formulation performance.