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• Elucidating nonlinear pharmacokinetics of telmisartan: Integration of target-mediated drug disposition and OATP1B3-mediated hepatic uptake in a physiologically based model

  Tsuchitani T., Tomaru A., Aoki Y., Ishiguro N., Tsuda Y., Sugiyama Y.

  CPT: Pharmacometrics and Systems Pharmacology 13 （ 7 ） 1224 - 1237 2024年07月

  　概要を見る

  Telmisartan, a selective inhibitor of angiotensin II receptor type 1 (AT1), demonstrates nonlinear pharmacokinetics (PK) when orally administered in ascending doses to healthy volunteers, but the underlying mechanisms remain unclear. This study presents a physiologically based pharmacokinetic model integrated with target-mediated drug disposition (TMDD-PBPK model) to explore the mechanism of its nonlinear PK. We employed the Cluster-Gauss Newton method for top-down analysis, estimating the in vivo Km,OATP1B3 (Michaelis–Menten constant for telmisartan hepatic uptake via Organic Anion Transporting Polypeptide 1B3) to be 2.0–5.7 nM. This range is significantly lower than the reported in vitro value of 810 nM, obtained in 0.3% human serum albumin (HSA) conditions. Further validation was achieved through in vitro assessment in plated human hepatocytes with 4.5% HSA, showing a Km of 4.5 nM. These results underscore the importance of albumin-mediated uptake effect for the hepatic uptake of telmisartan. Our TMDD-PBPK model, developed through a “middle-out” approach, underwent sensitivity analysis to identify key factors in the nonlinear PK of telmisartan. We found that the nonlinearity in the area under the concentration–time curve (AUC) and/or maximum concentration (Cmax) of telmisartan is sensitive to Km,OATP1B3 across all dosages. Additionally, the dissociation constant (Kd) for telmisartan binding to the AT1 receptor, along with its receptor abundance, notably influences PK at lower doses (below 20 mg). In conclusion, the nonlinear PK of telmisartan appears primarily driven by hepatic uptake saturation across all dose ranges and by AT1-receptor binding saturation, notably at lower doses.

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• The Effects of Jabara Juice on the Intestinal Permeation of Fexofenadine

  Han H., Akiyoshi T., Morita T., Tsuchitani T., Nabeta M., Yajima K., Imaoka A., Ohtani H.

  Biological and Pharmaceutical Bulletin 46 （ 12 ） 1745 - 1752 2023年

  ISSN  09186158

  　概要を見る

  Jabara juice and its component narirutin inhibit the activity of organic anion-transporting polypeptides (OATPs) 1A2 and OATP2B1, which are considered to play significant roles in the intestinal absorption of fexofenadine. In this study, we investigated the effects of jabara juice on the intestinal absorption of fexofenadine in mice and the inhibitory effects of jabara juice and narirutin on the permeation of fexofenadine using Caco-2 cell monolayers and LLC-GA5-COL300 cell monolayers. In the in vivo study, the area under the plasma concentration–time curve (AUC) of fexofenadine in mice was increased 1.8-fold by jabara juice. In the permeation study, 5% jabara juice significantly decreased the efflux ratio (ER) of fexofenadine for Caco-2 monolayers. Furthermore, the ERs of fexofenadine and digoxin, which is a typical substrate of P-glycoprotein (P-gp), for LLC-GA5-COL300 cell monolayers were decreased in a concentration-dependent manner by jabara juice extract, suggesting that jabara juice may increase the intestinal absorption of fexofenadine by inhibiting P-gp, rather than by narirutin inhibiting OATPs. The present study showed that jabara juice increases the intestinal absorption of fexofenadine both in vivo and in vitro. The intestinal absorption of fexofenadine may be altered by the co-administration of jabara juice in the clinical setting.

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• Mechanistic bottom-up estimation of passive drug absorption from the gastrointestinal tract: Comparison among primary cultured human intestinal cells, Caco-2 cells, artificial membrane, and animal scale-up

  Tsuchitani T., Akiyoshi T., Imaoka A., Ohtani H.

  International Journal of Clinical Pharmacology and Therapeutics 60 （ 5 ） 217 - 224 2022年05月

  ISSN  09461965

  　概要を見る

  Objective: The fraction of drug absorbed (Fa) from the intestine is an important parameter to characterize the pharmacokinetics of a drug. We aimed to search for an experimental system that provides the best parameters for estimating the effective permeability (Peff) used for the bottom-up prediction of Fa. Materials and methods: The absorption kinetics of 12 passively absorbed drugs were simulated by a compartment absorption transit (CAT) model using absorption parameters from four different experimental systems: human intestinal epithelial cell (HIEC) monolayer, Caco-2 monolayer, parallel artificial membrane permeability assay (PAMPA), and in situ rat intestinal perfusion. All absorption parameters were obtained from the literature. The in vitro apparent permeability coefficient (Papp) and rat in situ Peff were converted to human Peff using a bottom-up approach for each region, based on the morphological features of the human intestine. The simulated Fa values were compared to the respective observed values. Furthermore, plasma concentration profiles of the drugs were simulated by convolution using the time-course of the absorption rate simulated using the Peff values calculated from the HIEC Papp. Results: The Fa values were best predicted by using the Peff values calculated from HEIC, within a 1.3-fold range of observed Fa in 11 out of 12 drugs. The simulated Cmax values of pharmacokinetic simulation using HIEC Papp fell within a 1.5-fold range of observed values for all the drugs examined. Conclusion: The HIEC monolayer was identified as the most suitable permeation parameter for estimating Fa and Cmax using a morphological feature-based bottom-up approach.

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• Inhibitory Effects of Cranberry Juice and Its Components on Intestinal OATP1A2 and OATP2B1: Identification of Avicularin as a Novel Inhibitor

  Morita T., Akiyoshi T., Tsuchitani T., Kataoka H., Araki N., Yajima K., Katayama K., Imaoka A., Ohtani H.

  Journal of Agricultural and Food Chemistry 70 （ 10 ） 3310 - 3320 2022年03月

  ISSN  00218561

  　概要を見る

  Organic anion-transporting polypeptide (OATP) 1A2 and OATP2B1 mediate the intestinal absorption of drugs. This study aimed to identify fruit juices or fruit juice components that inhibit OATPs and assess the risk of associated food-drug interactions. Inhibitory potency was assessed by examining the uptake of [3H]estrone 3-sulfate and [3H]fexofenadine into HEK293 cells expressing OATP1A2 or OATP2B1. In vivo experiments were conducted using mice to evaluate the effects of cranberry juice on the pharmacokinetics of orally administered fexofenadine. Of eight examined fruit juices, cranberry juice inhibited the functions of both OATPs most potently. Avicularin, a component of cranberry juice, was identified as a novel OATP inhibitor. It exhibited IC50values of 9.0 and 37 μM for the inhibition of estrone 3-sulfate uptake mediated by OATP1A2 and OATP2B1, respectively. A pharmacokinetic experiment revealed that fexofenadine exposure was significantly reduced (by 50%) by cranberry juice. Cranberry juice may cause drug interactions with OATP substrates.

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• Using an online journal club to improve Asian speakers’ comfort in using English to discuss and understand research papers written in English

  Tsuchiya M., Saeteaw M., Subongkot S., Tharnpanich T., Konmun J., Nasu I., Shimanuki Y., Tsuchitani T., Ezura M., Hashiguchi K., Bryan J.C., Kawazoe H.

  Journal of Oncology Pharmacy Practice 2022年

  ISSN  10781552

  　概要を見る

  Introduction: This study aimed to evaluate the participants’ comfort in understanding research papers written in English and discussing such research in English via an Asian online journal club. Methods: A self-administered online survey was delivered to seven journal club meeting attendees from July 2020 to July 2021. A customer satisfaction analysis was performed to assess the association between the participants’ perspectives on program logistics and satisfaction. Results: The recovery rate was 37.0% (44/119). After participating in the journal club, the median scores of critical appraisal skills, knowledge and/or pharmaceutical care skills in clinical practice, and discussion skills in English (assessed using a seven-point Likert scale) improved significantly (compared to pre-participation median scores) from 4 (interquartile range [IQR]: 3–5) to 5 (IQR: 4–6), 5 (IQR: 4–5) to 5 (IQR: 5–6), and 4 (IQR: 2–5) to 5 (IQR: 3–5), respectively (P < 0.0001). The respondents also expressed great appreciation for the benefits and overall qualities of the journal club. Additionally, regarding patient care behavior after participation in the journal club, 34 (77.3%), 17 (38.6%), 16 (36.4%), and 14 (31.8%) respondents reported improvement in “drug information services,” “patient assessments,” “patient counseling,” and “multidisciplinary rounds,” respectively. Customer satisfaction analysis revealed that sharing information, mutual discussion, a shift system of presenters and co-chairs, and session duration should be improved as a matter of highest priority. Conclusion: The findings suggest that our program could be helpful for Asian pharmacists, pharmacy students, and faculty members of the department of pharmacy.

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