Yoshiyuki Shirasaka

Purpose This study aims to develop a physiologically based pharmacokinetic (PBPK) absorption model incorporating gastrointestinal (GI) fluid dynamics and to quantitatively evaluate the effects of GI fluid dynamics on the oral absorption of various drugs in humans. Methods By incorporating our previously developed physiologically based fluid kinetic (PBFK) model describing GI fluid dynamics into a PBPK absorption model, we constructed the Integrated Liquid and Intestinal Absorption Drug (ILIAD) model, which dynamically describes drug concentrations based on the GI disposition of both fluid and drugs. The scaling factors (SF) for membrane permeability, CYP3A-catalyzed metabolism, and P-gp-mediated efflux introduced into the ILIAD model were obtained as common parameters for all drugs through simultaneous optimization using the reported plasma concentration–time profiles of atenolol, midazolam, and talinolol. Results Simulation analysis using the ILIAD model accurately predicted the bioavailability and plasma concentration–time profile of various CYP3A and/or P-gp substrate drugs. Sensitivity analysis demonstrated that changes in GI fluid dynamics can lead to variations in GI fluid volume, resulting in altered drug absorption, particularly for low-permeability drugs. However, further analyses demonstrated that even high-permeability drugs may be affected by the GI fluid dynamics when they are substrates of CYP3A or P-gp. Conclusion Our ILIAD model is expected to be a useful tool for predicting oral drug absorption properties, including the effects of changes in GI fluid dynamics.

Metformin readily crosses the human placenta. However, the fetal-to-maternal plasma concentration ratio (F/M ratio) of metformin has been reported to be as low as 0.057 in rats. This study investigated the underlying mechanisms of these interspecies differences by examining the expression and function of candidate transporters, organic cation transporter 3 (OCT3/SLC22A3) and multidrug and toxin extrusion protein 1 (MATE1/SLC47A1), in the placenta across species. Expression analysis at gene and protein levels using RNA-sequencing and absolute quantification by LC-MS/MS revealed minimal species differences in placental OCT3 expression (less than 4-fold). In contrast, MATE1 showed almost exclusive expression in the rat placental labyrinth, but minimal or undetectable levels were observed in samples prepared from human placental villi and mouse placental labyrinth. To evaluate the function of the placental MATE1, we compared the placental transfer of two dual substrates of MATE1 and OCT3, metformin and 1-methyl-4-phenylpyridinium (MPP⁺), in pregnant rats and mice in the presence and absence of pyrimethamine, a MATE1 inhibitor. The pyrimethamine was dosed to reach the plasma concentration, which specifically inhibits MATE1 based on the measured IC₅₀ of pyrimethamine to rat MATE1 and OCT3, which were 0.015 and 100 μM, respectively. The F/M ratios of metformin and MPP⁺ in the absence of pyrimethamine were half or less in rats compared to mice. Notably, preadministration of pyrimethamine increased the F/M ratios of metformin and MPP⁺ by approximately 50% in rats but not mice. These findings demonstrate that functional placental MATE1 expression is specific to rats, which, in part, contributes to the low fetal transfer of cationic compounds compared with other species. This is of significant concern, as it suggests that nonclinical developmental and reproductive toxicity studies of MATE1 substrate drugs in rats may underestimate fetal exposure and toxicity when extrapolated to humans.

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.