Magnitude of Fruit Juice-Drug Interactions Due to Osmolality-Dependent Fluid Secretion: Differences among Apple, Orange, and Grapefruit Juices.

We recently reported that the gastrointestinal (GI) fluid volume is influenced by the solution osmolality, and proposed that this effect may play a role in beverage-drug interactions. Here, we investigated whether osmolality-dependent fluid secretion can explain the difference in the magnitudes of fruit juice-drug interactions depending on the type of fruit juice (grapefruit juice (GFJ), orange juice (OJ), and apple juice (AJ)). The osmolality of GFJ, OJ, and AJ used in this study was found to be 552, 686, and 749 mOsm/kg, respectively. Measurements of intestinal fluid movement following beverage administration by the in situ closed-loop technique revealed the following rank order for fluid volume in rat ileum: AJ > OJ > GFJ > purified water, suggesting that water movement is dependent on the osmolality of these beverages. Such changes in GI fluid volume are expected to alter the luminal drug concentration, potentially contributing to the magnitude of beverage-drug interactions. Indeed, in vivo pharmacokinetic study in rats revealed that the plasma concentration of atenolol, a low-permeability drug, was the highest after oral administration in purified water, followed by GFJ and OJ, and was the lowest after administration in AJ. In contrast, antipyrine, a high-permeability drug, showed no significant difference in plasma concentration after administration in purified water and fruit juices, suggesting that the absorption of high-permeability drugs is less affected by solution osmolality. Our findings indicate that differences in the magnitude of beverage-drug interactions can be at least partly explained by differences in the osmolality of the beverages ingested.

Effect of ingested fluid volume and solution osmolality on intestinal drug absorption: Impact on drug interaction with beverages.

It was recently shown that osmolality-dependent fluid movement is a significant factor causing the clinically observed apple juice (AJ)-atenolol interaction. Here we examined whether osmolality-dependent fluid movement may also explain the AJ volume dependence of the AJ-atenolol interaction. In Wistar rats, the luminal fluid volume after administration of different volumes of purified water (0.5 and 1.0 mL) gradually reduced to a similar steady-state level, while that after administration of different volumes of AJ (0.5 and 1.0 mL) increased and attained different apparent steady-state levels. It was hypothesized that osmolality-dependent fluid secretion would account for the volume dependence of the apparent steady-state. Indeed, the luminal concentration of FD-4, a non-permeable compound, after administration in AJ was attenuated depending upon the ingested volume, whereas that after administration in purified water was independent of the ingested fluid volume. An in vivo pharmacokinetic study in rats showed that co-administration of AJ and hyperosmotic solution (adjusted to the osmolality of AJ) with atenolol volume-dependently reduced the AUC and Cmax of atenolol significantly. These results show that osmolality-dependent variations in luminal fluid volume may indirectly influence the absorption characteristics of drugs, and can account for the observed volume dependence of beverage-drug interactions.

Multiple Transport Mechanisms Involved in the Intestinal Absorption of Metformin: Impact on the Nonlinear Absorption Kinetics.

The aim of this study was to investigate the contributions of multiple transport mechanisms to the intestinal absorption of metformin, focusing on OCT3, PMAT, THTR2, SERT and OCTN2. We also assessed the impact of these transporters on the nonlinear absorption of metformin. Uptake studies with MDCKII cells expressing OCT3, PMAT, THTR2 or SERT confirmed that metformin is a substrate of these transporters. Decynium22 strongly inhibited metformin uptake mediated by all the transporters. 7-Cyclopentyl inhibited OCT3- and THTR2-mediated uptake of metformin. AG835, thiamine and paroxetine specifically inhibited PMAT-, THTR2- and SERT-mediated uptake of metformin, respectively. Using these inhibitors, the relative contributions of OCT3, PMAT, THTR2, SERT, OCTN2 and others to the intestinal permeation of metformin across Caco-2 cells were estimated to be 9.77%, 9.68%, 22.2%, 1.52%, 0% and 0.66%, respectively. Concentration-dependent analysis of metformin uptake by Caco-2 cells revealed nonlinear kinetics with the similar Km(app) value to the value for THTR2. Further in situ absorption study demonstrated that rat intestinal permeability of metformin was significantly decreased in the presence of decynium22, 7-cyclopentyl and thiamine. The present study indicated that THTR2 is the major determinant of the nonlinear absorption of metformin, although multiple transport mechanisms contribute to its intestinal absorption.

Influence of osmolality on gastrointestinal fluid volume and drug absorption: potential impact on oral salt supplementation.

BACKGROUND: The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is the most frequent cause of hyponatremia in patients with cerebrovascular disease, and is often treated with oral salt tablets. However, we have shown that osmolality-dependent variations in gastrointestinal (GI) fluid volume can alter the concentration of a poorly permeable drug in the GI tract, potentially affecting its absorption. Here, we examined the effect of ingestion of hyperosmotic solution (10% NaCl) on drug concentration and absorption in the GI tract. METHODS: The effects of osmolality on luminal fluid volume and drug absorption in rat intestine (jejunum, ileum and colon) were examined by means of an in situ closed loop method using fluorescein isothiocyanate-dextran 4000 (FD-4) and atenolol. In vivo absorption in rats was determined by measuring the plasma concentration after oral administration of the test compounds dissolved in purified water or hyperosmotic solution (10% NaCl). RESULTS: Administration of hyperosmotic solution directly into the GI tract significantly increased the GI fluid volume, owing to secretion of water into the lumen. After administration in hyperosmotic solution, the luminal concentration of non-permeable FD-4 was significantly lower than the initial dosing concentration, whereas after administration in purified water, the luminal concentration exceeded the initial concentration. The fraction absorbed of atenolol was markedly lower after administration in hyperosmotic solution than after administration in purified water. An in vivo pharmacokinetic study in rats was consistent with these findings. CONCLUSIONS: Administration of hyperosmotic NaCl solution increased GI fluid volume and reduced the plasma level of orally administered atenolol. This may imply that oral salt tablets used to treat hyponatremia in SIADH patients could decrease the intestinal absorption of concomitantly administered drugs, resulting in lower plasma exposure.

Effect of Osmolality on the Pharmacokinetic Interaction between Apple Juice and Atenolol in Rats.

A recent clinical study reported that the ingestion of apple juice (AJ) markedly reduced the plasma concentration of atenolol; however, our in vitro study showed that atenolol may not be a substrate of organic anion transporting polypeptide 2B1 (OATP2B1), so this AJ-atenolol interaction cannot be explained by inhibition of OATP2B1. On the other hand, we more recently showed that the solution osmolality influences gastrointestinal (GI) water volume, and this may indirectly affect intestinal drug absorption. In this study, we examined whether the osmolality dependence of water dynamics can account for AJ-atenolol interactions by evaluating the GI water volume and the atenolol aborption in the presence of AJ in rats. Water absorption was highest in purified water, followed by saline and isosmotic mannitol solution, and the lowest in AJ, confirming that water absorption is indeed osmolality-dependent. Interestingly, AJ showed apparent water secretion into the intestinal lumen. The intestinal concentration of FD-4, a nonpermeable compound, after administration in AJ was lower than the initial concentration, whereas that in purified water was greater than the initial concentration. Further, the fraction of atenolol absorbed in intestine was significantly lower in AJ or hyperosmotic mannitol solution (adjusted to the osmolality of AJ) than after administration in purified water. Comparable results were observed in an in vivo pharmacokinetic study in rats. Our results indicate that orally administered AJ has a capacity to modulate luminal water volume depending on the osmolality, and this effect may result in significant AJ-atenolol interactions.

Association of the Clinical Subtype and Etiology for Delirium with the Outcome after Risperidone Monotherapy in Patients Having Cancer.

Background Delirium is the most frequent psychiatric syndrome in patients with advanced cancer, but its management is complicated by its multifactorial pathology. In this study, we investigated the association of the clinical subtypes, possible etiologies, and reversibility of delirium in patients having cancer with risperidone monotherapy. Methods This study included 16 inpatients with advanced cancer who were consecutively referred to psychiatric consultation service or palliative care team and were diagnosed with delirium by a psychiatrist. These patients were assessed using the Delirium Rating Scale Revised 98 (DRS-R98) at baseline and on a follow up visit (seventh day). The etiologies of delirium were determined using the Delirium Etiology Checklist. Oral risperidone was given once a day (0.5 or 1 mg/day) with routine clinical management. A detailed examination of the association between each clinical factor and their reversibility after risperidone treatment was examined retrospectively. Results Of the 15 patients (mean age 64.1? 9.5 years) whose data were available, 53% had hyperactive delirium and 47% had mixed delirium, while no patient showed hypoactive delirium. The most frequent etiology of delirium was metabolic/endocrine disturbance, drug intoxication, and systemic infection. In 10 patients (67%), remission of delirium was achieved, according to the DRS-R98. Neither clinical subtypes nor possible etiologies were associated with delirium reversibility after risperidone treatment. Conclusions Risperidone monotherapy is effective for treating delirium in patients with advanced cancer.