Combined Use of Flubromazepam and Stimulants: Blood and Oral Fluid Concentrations and Impact on Driving Ability.

"Designer" benzodiazepines (DBZDs) are becoming increasingly available in Europe, with the European Monitoring Centre of Drugs and Drug Addiction currently monitoring ∼30 new benzodiazepines. The following driving under the influence of drug (DUID) case describes the oral fluid (OF) and blood concentrations, as well as the observed effects after the combined use of stimulants and flubromazepam. Both OF, collected via the Intercept i2 collector (Immunalysis, Pomona, CA, USA), and blood (collected in containers with various stabilizers) were screened using a liquid chromatographic (LC) time-of-flight (TOF) mass spectrometric (MS-MS) method. In addition, various LC-MS-MS methods in multi-reaction monitoring mode were applied for confirmation and quantification. The OF and blood samples were taken 2 h 25 min and 9 h 19 min after the accident, respectively. OF contained 789 ng/mL amphetamine, 5,173 ng/mL MDMA, 168 ng/mL benzoylecgonine, 492 ng/mL cocaine, 134 ng/mL 4-methylmethcathinone (4-MMC) and traces of flubromazepam (less than limit of quantification (LLOQ); 2 ng/mL). The sodium-fluoride blood samples contained 19 ng/mL amphetamine, 284 ng/mL MDMA, 20 ng/mL MDA, 38 ng/mL benzoylecgonine, 4 ng/mL methylecgonine, 161 ng/mL flubromazepam and traces of 4-MMC (

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir.

Proton-pump inhibitors (PPIs), frequently prescribed to lower gastric acid secretion, often exert an effect on the absorption of co-medicated drug products. A previous study showed decreased plasma levels of the lipophilic drug ritonavir after co-administration with the PPI Nexium (40 mg esomeprazole), even though duodenal concentrations were not affected. The present study explored if a PPI-induced decrease in gastrointestinal (GI) fluid volume might contribute to the reduced absorption of ritonavir. In an exploratory cross-over study, five volunteers were given a Norvir tablet (100 mg ritonavir) orally, once without PPI pre-treatment and once after a three-day pre-treatment with the PPI esomeprazole. Blood samples were collected for eight hours to assess ritonavir absorption and magnetic resonance imaging (MRI) was used to determine the gastric and duodenal fluid volumes during the first three hours after administration of the tablet. The results confirmed that PPI intake reduced ritonavir plasma concentrations by 40%. The gastric residual volume and gastric fluid volume decreased by 41% and 44% respectively, while the duodenal fluid volume was reduced by 33%. These data suggest that the PPI esomeprazole lowers the available fluid volume for dissolution, which may limit the amount of ritonavir that can be absorbed. Although additional factors may play a role, the effect of PPI intake on the GI fluid volume should be considered when simulating the absorption of poorly soluble drugs like ritonavir in real-life conditions.

The mechanisms of pharmacokinetic food-drug interactions - A perspective from the UNGAP group.

The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group "Food-Drug Interface", the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspectives.

Impact of regional differences along the gastrointestinal tract of healthy adults on oral drug absorption: An UNGAP review.

Oral administration is the most common route of drug delivery. The absorption of a drug from the gut into the bloodstream involves disintegration of the solid dosage form, dissolution of the active pharmaceutical ingredient and its transport across the gut wall. The efficiency of these processes is determined by highly complex and dynamic interplay between the gastrointestinal tract, the dosage form and the API. The European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) aims to improve our understanding of intestinal drug absorption by creating a multidisciplinary Network of researchers from academia and industry engaging in scientific discussions. As part of the basis for the UNGAP project, this review aims to summarize the current knowledge on anatomy and physiology of the human gastrointestinal tract with emphasis on human studies for the evaluation of the regional drug absorption and the prediction of oral dosage form performance. A range of factors and methods will be considered, including imaging methods, intraluminal sampling and, models for predicting segmental/regional absorption. In addition, in vitro and in silico methods to evaluate regional drug absorption will be discussed. This will provide the basis for further work on improving predictions for the in vivo behavior of drug products in the gastrointestinal tract.

Gastric and Duodenal Diclofenac Concentrations in Healthy Volunteers after Intake of the FDA Standard Meal: In Vivo Observations and in Vitro Explorations.

This study investigated gastrointestinal drug concentrations of the weakly acidic drug diclofenac when dosed to healthy volunteers after intake of the FDA standard meal. In gastrointestinal aspiration studies, postprandial conditions are usually achieved using liquid or homogenized meals. However, these liquid meals may have a substantially different impact on the gastrointestinal physiology compared to a solid meal. To evaluate the effect of a solid meal on the gastrointestinal behavior of diclofenac, five healthy volunteers were recruited into a clinical study. Twenty minutes prior to diclofenac ingestion (Cataflam, 50 mg of potassium diclofenac), the volunteers were asked to eat a solid meal with the following composition corresponding to the FDA standard meal: 2 eggs, 2 bacon strips, 2 toasts, 4 ounces of hash brown potatoes, and 8 ounces of milk. Gastric and duodenal fluids were collected as a function of time, and blood samples were collected to link the gastrointestinal behavior to systemic exposure. In vivo observations were complemented with in vitro research to obtain a mechanistic understanding of diclofenac's intraluminal behavior. Ingestion of the solid meal resulted in intraluminal pH-profiles similar to earlier studies with a liquid meal. However, intraluminal drug disposition differed. In the stomach, a substantial fraction of diclofenac appeared dissolved, despite an unfavorable acidic pH. Successive in vitro tests suggested that the dissolution of diclofenac is higher in the complex gastric medium resulting from FDA standard meal ingestion compared to liquid meal ingestion. Despite the favorable pH and in contrast to a previous study with a liquid meal, significant amounts of non-dissolved diclofenac were observed in the intestine. Further in vitro tests revealed adsorption of dissolved diclofenac molecules to bacon fragments present in the FDA standard meal. This adsorption negatively affected the permeation of diclofenac across a physical barrier, suggesting that in vivo absorption is affected as well. Being the first time a gastrointestinal aspiration study is combined with the administration of a solid meal, the present study demonstrates that the intraluminal behavior of diclofenac (and possibly other drugs) heavily depends on the consistency and composition of the accompanied meal.

Exploring gastric drug absorption in fasted and fed state rats.

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.

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

OBJECTIVES: 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. METHODS: Six healthy volunteers were given a capsule of 500 mg of quercetin with 240 ml of water. Duodenal fluids were collected using the intraluminal sampling technique for 4 h and analysed by LC-MS/MS. KEY FINDINGS: Phase-II metabolites of quercetin were detected and quantified in aspirated intestinal fluids. Metabolites appeared almost immediately after administration, indicating an intestinal metabolism and apical excretion into the lumen. Quercetin-3'-O-glucuronide was found to be the main intestinal metabolite. Our results could not conclude on the enterohepatic recycling of quercetin or its metabolites, although several individual profiles showed distinctive peaks. CONCLUSIONS: This study highlights the intestinal metabolism and excretion of quercetin and its conjugates in humans and gives insights into the relevant concentrations which should be used to investigate potential food-drug interactions in vitro.

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.

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 stomach's 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.

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. Indinavir's 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 indinavir's 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.

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.