Anders Carlsson

The gastrointestinal microbiota as a site for the biotransformation of drugs

There are 100 trillion microbes in the human gastrointestinal tract with numbers increasing distally. These microbiota secrete a diverse array of enzymes (primarily for carbohydrate and protein fermentation) giving them substantial metabolic potential which can have major implications for drug stability. At least thirty drugs which are, or have been, available commercially, were subsequently shown to be substrates for these bacterial enzymes, and with increasing numbers of new and existing drugs having the potential for contact with the distal gut (through modified release systems or poor solubility/permeability), many more are expected to be discovered. The major concern with bacterial drug degradation is the behaviour of the metabolite; is it more or less active than the parent compound, or has toxicity resulted? For example, there were eighteen deaths in 1993 due to a drug interaction in which a toxic drug metabolite was produced by bacterial fermentation. Thus, the objective of this review is the provision of a comprehensive overview of this area; the gastrointestinal microbiota, their drug substrates and metabolic mechanisms, and approaches to studying this further are discussed.

The Effects of Food on the Dissolution of Poorly Soluble Drugs in Human and in Model Small Intestinal Fluids

PurposeThis study was conducted to determine the effect of food on drug solubility and dissolution rate in simulated and real human intestinal fluids (HIF).MethodsDissolution rate obtained via the rotating disk method and saturation solubility studies were carried out in fed and fasted state HIF, fed dog (DIF), and simulated (FeSSIF) intestinal fluid for six aprotic low solubility drugs. The intestinal fluids were characterized with respect to physical–chemical characteristics and contents.ResultsFed HIF provided a 3.5- to 30-times higher solubility compared to fasted HIF and FeSSIF, whereas fed DIF corresponded well (difference of less than 30%) to fed HIF. The increased solubility of food could mainly be attributed to dietary lipids and bile acids. The dissolution rate was also 2 to 7 times higher in fed HIF than fasted HIF. This was well predicted by both DIF and FeSSIF (difference of less than 30%).ConclusionsIntestinal solubility is higher in fed state compared to fasted state. However, the dissolution rate does not increase to the same extent. Dog seems to be a good model for man with respect to dissolution in the small intestine after intake of a meal, whereas FeSSIF is a poorer means of determining intestinal saturation solubility in the fed state.

Simultaneous probing of swelling, erosion and dissolution by NMR-microimaging—Effect of solubility of additives on HPMC matrix tablets

Extensive studies of extended release tablets based on hydrophilic polymers have illuminated several aspects linked to their functionality. However, in some respects key factors affecting the mechanisms of release are yet unexplored. In the present study, a novel NMR-microimaging method has been used to study the influence of the solubility of additives in extended release hydroxypropyl methylcellulose (HPMC) matrix tablets. During the course of the tablet dissolution the movement of the swelling and erosion fronts were studied simultaneously to the release of both polymer and additives. Moreover, the focused beam reflectance measurement (FBRM) technology was for the first time assessed for both release and dissolution rate studies of poorly soluble particles. The studied formulations comprised solely HPMC, 40% HPMC and 60% mannitol (Cs=240 mg/ml) and 40% HPMC and 60% dicalcium phosphate (DCP) (Cs=0.05 mg/ml). The dissolution rate of the tablets was highest for the HPMC/mannitol formulation, followed by HPMC/DCP and plain HPMC tablet. A contrasting order was found regarding the degree and kinetics of swelling. The results were interpreted in light of how the mass transport in the gel layer is influenced by the solubility of additives. A mechanistic model, considering osmotic pressure gradient and the effective diffusion of the dissolution medium in the gel is proposed.

Drug Solubility in Luminal Fluids from Different Regions of the Small and Large Intestine of Humans

The purpose of this work was to study the solubility of two drugs with different physicochemical properties in luminal fluids obtained from various regions of the human gastrointestinal (GI) tract and to determine the most important luminal parameters influencing their solubility. Jejunal fluids were aspirated from healthy volunteers via an oral intubation tube. Ileal and colonic fluids were obtained from patients undergoing GI surgery. Stoma fluids were also retrieved from patients. pH and buffer capacity of all fluids were determined. Saturation solubility of prednisolone (unionisable) and mesalamine (5-aminosalicylic acid) (zwitterionic) was measured. Mean solubility of prednisolone in the different luminal fluids was 0.50 mg/mL (±0.05) and did not vary significantly between the different regions of the GI tract (ANOVA, p > 0.05). No correlation between prednisolone solubility and jejunal bile salt content was found. Mesalamine solubility increased down the GI tract: 1.97 (±0.25), 3.26 (±0.08), 6.24 (±1.13) and 7.95 (±0.21) mg/mL in jejunal, ileal, ascending and transverse/descending colonic fluids respectively. Buffer capacity also increased and in one patient was observed to range from 6.4 to 28.6 reaching 44.4 mM/L/pH unit in ileal, ascending and transverse/descending colon fluids respectively. Mesalamine solubility was found to be dependent on both buffer capacity and pH, with buffer capacity being the most important (standardized coefficient β = 0.849, p < 0.0001) compared to pH (β = 0.219, p < 0.05). For drugs delivered as modified release formulations it is important to consider solubility in different regions of the GI tract as significant differences can arise which will ultimately influence drug bioavailability.

Degradation kinetics of metronidazole and olsalazine by bacteria in ascending colon and in feces of healthy adults

PURPOSE To compare the degradation kinetics of metronidazole and olsalazine by the bacteria of ascending colon and the bacteria of feces of healthy adults. METHODS Contents of the ascending colon of seven healthy adults were collected under conditions simulating the bioavailability/bioequivalence studies in the fasted and in the fed states on a crossover basis. Material from the contents of the ascending colon was prepared by ultracentrifuging and diluting the precipitate with a volume of normal saline equivalent to that of the supernatant. Fecal material was prepared from feces of three healthy adults collected at two occasions that were separated by at least 6 months. Ex vivo drug degradation kinetics were evaluated under anaerobic conditions. RESULTS Mean half-lives of metronidazole degradation in material from the contents of the ascending colon collected in the fasted state and in fecal material were 16.1 and 2.4 min, respectively (p<0.001). The corresponding numbers for olsalazine were 57.8 and 9.2 min, respectively (p<0.001). Both compounds were stable in material from the contents of ascending colon collected in the fed state. CONCLUSIONS Compared with data in fecal material, degradation of metronidazole and olsalazine in material from the contents of the ascending colon is significantly slower and it becomes non-significant during the arrival of fresh food remnants in the region.

Stability of esomeprazole capsule contents after in vitro suspension in common soft foods and beverages.

Study Objective. To determine the in vitro stability of esomeprazole pellets from an opened capsule after suspension in various common soft foods and beverages.

Pharmacokinetics, Tissue Distribution and Metabolism of Intravenously Administered Digalactosyldiacylglycerol and Monogalactosyldiacylglycerol in the Rat

AbstractA bilayer forming galactolipid, digalactosyldiacylglycerol (DGalDG) has been identified as a tool with suitable physicochemichal properties for pharmaceutical formulation work. One possible application is as a carrier for liposome entrapped drugs for intravenous administration. The fate of intravenously administered galactolipids is not known. In this study liposomal dispersions of galactolipids, containing [3H]fatty acid labelled DGalDG or monogalactosyldiacylglycerol (MGalDG) were injected intravenously in the rat and the disappearance from blood and uptake by tissues were examined. The T1/2 of [3H]DGalDG in plasma was 3 to 5 minutes. Of the tissues examined (liver, spleen, kidneys, lung, heart, stomach, upper and lower small intestine and colon), the liver contained the highest radioactivity per g tissue after both 15 min. and 4 h. Autoradiographic examinations after 15 min, 1 h and 4 h showed that the uptake of radiolabeled DGalDG and MGalDG occurred mainly to the hepatocytes. Less than 6 % of...