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Population pharmacokinetics of everolimus in renal transplant recipients receiving long-term multiple immunosuppressive therapy Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2024-03-12 Tomoyuki Sakaue, Kazuhiro Yamamoto, Kotaro Itohara, Yumi Kitahiro, Takahito Endo, Naoki Yokoyama, Takeshi Ishimura, Tomohiro Omura, Ikuko Yano
Everolimus is used for immunosuppression after renal transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model of everolimus using therapeutic drug monitoring (TDM) data of patients under long-term multiple immunosuppressive therapy, including tacrolimus. To develop the model, 185 renal transplant recipients with 3358 everolimus blood concentrations during a median postoperative
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Quantitative prediction of CYP3A induction-mediated drug-drug interactions in clinical practice Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2024-03-11 Haruka Tsutsui, Motohiro Kato, Shino Kuramoto, Kouichi Yoshinari
There have been no reports on the quantitative prediction of CYP3A induction-mediated decreases in AUC and for drug candidates identified as a “victims” of CYP3A induction. Our previous study separately evaluated the fold-induction of hepatic and intestinal CYP3A by known inducers using clinical induction data and revealed that we were able to quantitatively predict the ratio (AUCR) of a few CYP3A
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Prediction of drug-drug interaction risk of P-glycoprotein substrate in drug discovery Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2024-03-11 Yasuto Kido, Isamu Nanchi, Takanobu Matsuzaki, Ryosuke Watari, Hayato Kiyohara, Naomi Seki, Tomohiko Okuda
We aimed to predict the drug-drug interaction (DDI) risk of P-glycoprotein (P-gp) substrates by using P-gp expressing LLC-PK1 cells and its knockout mice (KO). The area under the curve (AUC) of 16 marketed drugs and plasma concentration (C) of 207 screening compounds, with corrected efflux ratio (CER) ≥ 2, were compared between P-gp KO mice and wild type mice (WT). At permeability (Papp) ≥ 10 × 10
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Impact of miR-222-3p-mediated downregulation of arylacetamide deacetylase on drug hydrolysis and lipid accumulation Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2024-03-06 Yoshiyuki Sakai, Tatsuki Fukami, Shinsaku Tokumitsu, Masataka Nakano, Shimon Nakashima, Yuichiro Higuchi, Shotaro Uehara, Nao Yoneda, Hiroshi Suemizu, Miki Nakajima
Arylacetamide deacetylase (AADAC) is involved in drug hydrolysis and lipid metabolism. In 23 human liver samples, no significant correlation was observed between AADAC mRNA (19.7-fold variation) and protein levels (137.6-fold variation), suggesting a significant contribution of post-transcriptional regulation to AADAC expression. The present study investigated whether AADAC is regulated by microRNA
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In vitro demonstration of antedrug mechanism of a pharmacokinetic booster to improve CYP3A4 substrates by CYP3A4-mediated metabolism inhibition Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2024-03-02 Makoto Kataoka, Sae Takenaka, Shota Fujii, Takato Masada, Keiko Minami, Toshihide Takagi, Masaaki Omote, Kentaro Kawai, Shinji Yamashita
We previously reported novel benzyl-ether derivatives with an imidazole ring and a hydroxyl group (A-01) or carboxyl group (B-01) and esters (2 esters of A-01, and 7 esters of B-01) as pharmacokinetics (PK) boosters. This study demonstrates how these ester compounds embody the concept of a safe pharmacokinetic booster, with potent and transient inhibition of CYP3A4-mediated drug metabolism. As a model
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Application of machine learning techniques in population pharmacokinetics/pharmacodynamics modeling Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2024-02-17 Mizuki Uno, Yuta Nakamaru, Fumiyoshi Yamashita
Population pharmacokinetics/pharmacodynamics (pop-PK/PD) consolidates pharmacokinetic and pharmacodynamic data from many subjects to understand inter- and intra-individual variability due to patient backgrounds, including disease state and genetics. The typical workflow in pop-PK/PD analysis involves the determination of the structure model, selection of the error model, analysis based on the base
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DMPK perspective on quantitative model analysis for chimeric antigen receptor cell therapy: Advances and challenges Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2024-02-14 Akihiko Goto, Yuu Moriya, Miyu Nakayama, Shinji Iwasaki, Syunsuke Yamamoto
Chimeric antigen receptor (CAR) cells are genetically engineered immune cells that specifically target tumor-associated antigens and have revolutionized cancer treatment, particularly in hematological malignancies, with ongoing investigations into their potential applications in solid tumors. This review provides a comprehensive overview of the current status and challenges in drug metabolism and pharmacokinetics
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Transcript abundance of hepatic drug-metabolizing enzymes in two dog breeds compared with 14 species including humans Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2024-01-26 Yasuhiro Uno, Osamu Yamato, Hiroshi Yamazaki
Drug-metabolizing enzymes are important in drug development and therapy, but have not been fully identified and characterized in many species, lines, and breeds. Liver transcriptomic data were analyzed for phase I cytochromes P450, flavin-containing monooxygenases, and carboxylesterases and phase II UDP-glucuronosyltransferases, sulfotransferases, and glutathione -transferases. Comparisons with a variety
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Unveiling the intra-tumor fate of trastuzumab deruxtecan in a xenograft model to support its mechanism of action Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2024-01-23 Yoko Nagai, Masataka Oitate, Takahiro Shibayama, Hideo Takakusa, Nobuaki Watanabe
Trastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate used for cancer treatment comprising an anti-human epidermal growth factor receptor type 2 (HER2) antibody and the topoisomerase I inhibitor DXd. The present study investigated the intratumor fate of T-DXd. Fluorescence-labeled T-DXd was found to accumulate in tumors of HER2-positive tumor xenograft mice and was observed to be distributed
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Physiologically based pharmacokinetic modeling to predict the clinical effect of azole antifungal agents as CYP3A inhibitors on azelnidipine pharmacokinetics Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2024-01-23 Akiko Watanabe, Masakatsu Kotsuma
In this study, a physiologically based pharmacokinetic (PBPK) model of the cytochrome P450 3A (CYP3A) substrate azelnidipine was developed using and clinical data to predict the effects of azole antifungals on azelnidipine pharmacokinetics. Modeling and simulations were conducted using the Simcyp™ PBPK simulator. The azelnidipine model consisted of a full PBPK model and a first-order absorption model
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Predicting muscarinic receptor occupancy in human bladder mucosa from urinary concentrations of antimuscarinic agents for overactive bladder Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2024-01-15 Mizuki Shiho, Gaku Akashita, Eriko Nakatani, Shimako Tanaka, Shizuo Yamada, Takashi Okura
To assess the pharmacologically relevant and selective muscarinic receptor occupancy in the bladder mucosa, we considered not only plasma drug concentrations but also urinary drug concentrations. The purpose of this study was to predict muscarinic receptor occupancy in the human bladder mucosa based on urinary concentrations in response to clinical dosages of antimuscarinic agents used to treat overactive
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Preferential meropenem absorption activated by 1α,25-dihydroxyvitamin D3 and shared with foscarnet, a phosphate transporter substrate, in the rat ileum Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2024-01-11 Toshihide Saito, Yuichi Ichimura, Masako Oda, Hiroshi Saitoh
Meropenem (MEPM) is used for the treatment of serious infectious diseases solely as. Injectable Therefore, the development of an oral formulation would expand its clinical utility. To this end, an exact understanding of the absorption characteristics of MEPM is essential. In this study, MEPM absorption in the rat small intestine was investigated using an in situ loop technique and an in vitro diffusion
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Applications of model simulation in pharmacological fields and the problems of theoretical reliability Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2024-01-04 Yoshiaki Kariya, Masashi Honma
The use of mathematical models has become increasingly prevalent in pharmacological fields, particularly in drug development processes. These models are instrumental in tasks such as designing clinical trials and assessing factors like efficacy, toxicity, and clinical practice. Various types of models have been developed and documented. Nevertheless, emphasizing the reliability of parameter values
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Sodium citrate buffer improves pazopanib solubility and absorption in gastric acid-suppressed rat model Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2024-01-03 Huda Jassim Muhammad, Tsutomu Shimada, Arimi Fujita, Yoshimichi Sai
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Air–liquid interface culture and modified culture medium promote the differentiation of human induced pluripotent stem cells into intestinal epithelial cells Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-12-31 Kotaro Shirai, Shimeng Qiu, Hanako Minowa, Tadahiro Hashita, Takahiro Iwao, Tamihide Matsunaga
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Rare but impaired flavin-containing monooxygenase 3 (FMO3) variants reported in a recently updated Japanese mega-databank of genome resources Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-12-22 Makiko Shimizu, Miaki Makiguchi, Eiji Hishinuma, Sakae Saito, Masahiro Hiratsuka, Hiroshi Yamazaki
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Quantification of fluticasone propionate in human plasma by LC–MS/MS and its application in the pharmacokinetic study of nasal spray at clinical doses Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-12-11 Aya Yamagata, Rena Adachi, Akitomo Yokokawa, Tomomi Furihata, Hiromi Shibasaki
We developed a method for quantifying fluticasone propionate (FP) using general-purpose liquid chromatography–tandem mass spectrometry equipment to measure the plasma concentration of FP for the pharmacokinetic study of FP following the administration of a prescribed nasal spray dose (100 μg). Using ammonium acetate (0.01 M)–formic acid (pH 2.9; 499:1, v/v) and methanol as the mobile phase, 3 pg/mL
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Cross-species drug metabolism and impact of metabolic stability testing under anaerobic condition on predicting pharmacokinetics of keto-enol containing compound in humans Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-11-21 Takushi Kanazu, Junto Tamada, Susumu Kume, Tohru Mizutare
After oral administration of [14C]-S-1360 in rats and dogs, [14C]-S-1360 was absorbed rapidly and the bioavailability was 93.7% in rats and 75.1% in dogs. Based on the results in animals, good systemic exposure would be expected in humans. In contrast to the expectation, the exposure was low in healthy volunteers compared to the exposure expected. In addition, human mass balance study using [14C]-S1360
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Physiologically based pharmacokinetic model analysis of the inhibitory effect of vonoprazan on the metabolic activation of proguanil Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-11-07 Kenjiro Okubo, Toshiyuki Kudo, Sae Yoshihara, Yu Nakabayashi, Kana Nakauchi, Akimi Tanaka, Moe Saito, Ayumi Tsujisawa, Hitomi Goda, Yoshiaki Yamagishi, Chinatsu Otake, Kosho Makino, Hideyo Takahashi, Kiyomi Ito
We previously reported that repeated oral administration of vonoprazan (VPZ) followed by oral administration of proguanil (PG) in healthy adults increased blood concentration of PG and decreased blood concentration of its metabolite cycloguanil (CG) compared with administration of PG alone. In this study, we investigated whether this interaction can be quantitatively explained by VPZ inhibition of
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Improvement of transdermal absorption rate by nonthermal biocompatible atmospheric pressure plasma Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-10-31 Byoung-Choul Kim, Juie Nahushkumar Rana, Eun Ha Choi, Ihn Han
Nonthermal biocompatible plasma (NBP) is a promising option for improving medication absorption into the human skin. Currently, most plasma devices for cosmetics employ a floating-electrode plasma source for treating the skin. Human skin serves as the ground electrode in the floating-electrode plasma discharge, and discharge occurs between the skin and electrodes of the device. In this in vitro study
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Construction of a fused grid-based CYP2C18-Template system and its application to drug metabolism Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-10-20 Yasushi Yamazoe, Kouichi Yoshinari
Detailed estimation of cytochrome P450 (CYP)-mediated metabolisms of medicine and other chemicals is necessary for the efficacy and safety assessments. Data on the metabolisms mediated by minor CYP enzymes like CYP2C18 are often not available in metabolisms and safety assessments of chemicals except for medical drugs developed recently. A ligand-accessible space in the active site of human CYP2C18
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Exposure-response analysis of the efficacy and safety of esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with or without diabetic kidney disease Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-10-19 Kazutaka Yoshihara, Masato Fukae, Helen Kastrissios, Russell Wada, Takako Shimizu
Background Esaxerenone is a novel non-steroidal mineralocorticoid receptor blocker. Here, we assessed efficacy and safety exposure-response relationships of esaxerenone and its covariates and thereby justified the recommended dosage regimens, focusing on the safety benefits of up-titration regimen in patients at higher risk for increased serum potassium (sK+). Methods The relationships between model-derived
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Food effects on oral drug absorption: Recent advances in understanding mechanisms and quantitative prediction Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-10-16 Yoshiyuki Shirasaka, Atsushi Kambayashi
Abstract not available
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Establishment of human intestinal organoids derived from commercially available cryopreserved intestinal epithelium and evaluation for pharmacokinetic study Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-10-08 Kentaro Okada, Jumpei Yokota, Tomoki Yamashita, Tatsuya Inui, Wataru kishimoto, Hiroshi Nakase, Hiroyuki Mizuguchi
Human intestinal organoids (HIOs) have been reported to exert their functions in a way that mimics living organs, and HIOs-derived monolayers are expected to be applied to in vitro intestinal pharmacokinetic studies. However, HIOs are established from human tissue, which raises issues of availability and ethics. In the present study, to solve these problems, we have established intestinal organoids
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Quantitative prediction of transporter-mediated drug-drug interactions using the mechanistic static pharmacokinetic (MSPK) model Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-10-07 Satoshi Asano, Chie Kurosaki, Yuko Mori, Ryota Shigemi
Guidance/guidelines on drug-drug interactions (DDIs) have been issued in Japan, the United States, and Europe. These guidance/guidelines provide decision trees for conducting metabolizing enzyme-mediated clinical DDI studies; however, the decision trees for transporter-mediated DDIs lack quantitative prediction methods. In this study, the accuracy of a net-effect mechanistic static pharmacokinetics
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Quantitation and characterization of glucosylsphingosine in cerebrospinal fluid (CSF), plasma, and brain of monkey model with Gaucher disease Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-09-15 Sho Sato, Shin-ichi Matsumoto, Yohei Kosugi
Treatment with conduritol-β-epoxide (CBE) in preclinical species is expected to be a powerful approach to generate animal models of Gaucher disease (GD) and Parkinson's disease associated with heterozygous mutations in Glucocerebrosidase (GBA-PD). However, it is not fully elucidated how quantitatively the change in glucosylsphingosine (GlcSph) levels in cerebrospinal fluid (CSF) correlates with that
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A model-based pharmacokinetic assessment of drug–drug interaction between tacrolimus and nirmatrelvir/ritonavir in a kidney transplant patient with COVID-19 Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-09-01 Takeshi Tomida, Kotaro Itohara, Kazuhiro Yamamoto, Takeshi Kimura, Kohei Fujita, Atsushi Uda, Yumi Kitahiro, Naoki Yokoyama, Yoji Hyodo, Tomohiro Omura, Ikuko Yano
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Simple confirmation methods for rare but impaired variants of human flavin-containing monooxygenase 3 (FMO3) found in an updated genome resource databank Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-08-23 Makiko Shimizu, Miaki Makiguchi, Yuka Yokota, Erika Shimamura, Moegi Matsuta, Yuria Nakamura, Mizuki Harano, Hiroshi Yamazaki
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Analysis of the interplay of physiological response to food intake and drug properties in food-drug interactions Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-06-12 Sheena Sharma, Clark Kogan, Manthena V.S. Varma, Bhagwat Prasad
The effect of food on oral drug absorption is determined by the complex interplay among gut physiological factors and drug properties. The currently used dissolution testing and classification systems (biopharmaceutics classification system, BCS or biopharmaceutics drug disposition classification system, BDDCS) do not account for dynamic changes in gastrointestinal physiology caused by food intake
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Phosphate buffer interferes dissolution of prazosin hydrochloride in compendial dissolution testing Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-06-10 Hiroshi Sudaki, Katsuyoshi Fujimoto, Koichi Wada, Kiyohiko Sugano
The purpose of this study was to elucidate the lack of supersaturation behavior in the dissolution profile of prazosin hydrochloride (PRZ-HCl) in the compendial dissolution test. The equilibrium solubility was measured by a shake-flask method. Dissolution tests were performed by a compendial paddle method with a phosphate buffer solution (pH 6.8, 50 mM phosphate). The solid form of the residual particles
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Population pharmacokinetics of esaxerenone, a novel non-steroidal mineralocorticoid receptor blocker, in patients with essential hypertension, patients with diabetic nephropathy, and healthy volunteers Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-06-07 Kazutaka Yoshihara, Masato Fukae, Helen Kastrissios, Russell Wada, Takako Shimizu, Hitoshi Ishizuka
Objectives Esaxerenone is a novel, non-steroidal mineralocorticoid receptor (MR) blocker with improved selectivity and affinity for MR. The objectives of this study were to model the population pharmacokinetics of esaxerenone in a diverse population and to evaluate the effect of covariates on pharmacokinetics parameters. Methods A total of 8263 plasma esaxerenone concentrations from 166 healthy volunteers
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Drugs that induce and inhibit cytochrome P450. A study with real-world evidence Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-06-04 Luis Fernando Valladales-Restrepo, Juan Alberto Ospina-Cano, Brayan Stiven Aristizábal-Carmona, Jorge Enrique Machado-Alba
The aim was to determine the prescription patterns of cytochrome P450-inducing and -inhibiting drugs and their contraindicated and major pharmacological interactions in a group of patients from Colombia. This cross-sectional study included patients who received drugs that induce or inhibit metabolism and examined their contraindicated and major pharmacological interactions. The patients were identified
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Population pharmacokinetic modeling of treosulfan and rationale for dose recommendation in children treated for conditioning prior to allogeneic hematopoietic stem cell transplantation Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-05-30 Xieran Li, Krzysztof Kalwak, Rita Beier, Jochen Kehne, Ann-Kristin Möller, Joachim Baumgart, Dietrich W. Beelen, Ralf A. Hilger, Ajay Vora, Karl-Walter Sykora
Intravenously infused treosulfan was evaluated in adult and pediatric patients for conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. A population pharmacokinetic (PK) model was initially developed on 116 adult and pediatric PK profiles from historical trials, to support treosulfan dose recommendations for children in 2 prospective trials. The aim was to assess and update
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Contribution analysis of metabolic tissues on systemic exposure of an active metabolite after oral administration of verapamil using a stable isotope-labeled compound Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-05-19 Makoto Kataoka, Shota Ohshiro, Keiko Minami, Tsubasa Hasegawa, Haruki Higashino, Toshihide Takagi, Kazutaka Togashi, Kuninori Mutaguchi, Shinji Yamashita
The present study illustrates the advantage of an isotope-IV study for the contribution analysis of metabolic tissues on systemic exposure of metabolites. A model parent drug, verapamil (VER), and its metabolite, norverapamil (Nor-VER), were used. This isotope-IV study used rats with and without the pre-treatment of the CYP inhibitor 1-aminobenzotriazole (ABT), was performed by the oral administration
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New in vitro screening system to detect drug-induced liver injury using a culture plate with low drug sorption and high oxygen permeability Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-04-26 Akinori Takemura, Sanae Ishii, Yugo Ikeyama, Katsuhiro Esashika, Jun Takahashi, Kousei Ito
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Apple-derived extracellular vesicles modulate the expression of human intestinal bile acid transporter ASBT/SLC10A2 via downregulation of transcription factor RARα Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-04-25 Shinya Usui, Qiunan Zhu, Hisakazu Komori, Yui Iwamoto, Takumi Nishiuchi, Yoshiyuki Shirasaka, Ikumi Tamai
Purpose Plant-derived extracellular vesicles (EVs) have been reported to exert biological activity on intestinal tissues by delivering their contents into intestinal cells. We previously reported that ASBT/SLC10A2 mRNA was downregulated by apple-derived extracellular vesicles (APEVs). ASBT downregulation is effective in the treatment of cholestasis and chronic constipation, similar to the beneficial
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Characterization of LysoTracker Red uptake by in vitro model cells of the outer blood-retinal barrier: Implication of lysosomal trapping with cytoplasmic vacuolation and cytotoxicity Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-04-23 Yuma Tega, Toshinari Takeuchi, Masatoshi Nagano, Reina Makino, Yoshiyuki Kubo, Shin-ichi Akanuma, Ken-ichi Hosoya
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Development of a fluorescent-labeled trapping reagent to evaluate the risk posed by acyl-CoA conjugates Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-04-10 Chikako Shibazaki, Tadahiko Mashino, Tomoyuki Ohe
Although acyl-CoA conjugates are known to have higher reactivity than acyl glucuronides, few studies have been conducted to evaluate the risk of the conjugates. In the present study, we aimed to develop a trapping assay for acyl-CoA conjugates using trapping reagents we have developed previously. It was revealed that Cys-Dan, which has both a thiol and an amino group, was the most effective in forming
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Corrigendum to <[Drug Metabolism and Pharmacokinetics Volume 41 (2021) 100408]> Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-04-01 Ning Ding, Syunsuke Yamamoto, Ikumi Chisaki, Miyu Nakayama, Shin-ichi Matsumoto, Hideki Hirabayashi
Abstract not available
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Ferulic acid prevents Diosbulbin B-induced liver injury by inhibiting covalent modifications on proteins Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-03-30 Huiling Chen, Chenchen Liu, Meng Li, Yida Zhang, Zhendong Wang, Qiyao Jiang, Jianxin Wang, Qi Wang, Yue Zhuo
Diosbulbin B (DIOB) has been reported to cause serious liver injury. However, in traditional medicine, DIOB-containing herbs are highly safe in combination with ferulic acid (FA)-containing herbs, suggesting potential neutralizing effect of FA on the toxicity of DIOB. DIOB can be metabolized to generate reactive metabolites (RMs), which can covalently bind to proteins and lead to hepatoxicity. In the
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Physiologically based pharmacokinetic (PBPK) model that describes enhanced FcRn-dependent distribution of monoclonal antibodies (mAbs) by pI-engineering in mice Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-03-22 Sotaro Naoi, Mizuki Yamane, Takayuki Nemoto, Motohiro Kato, Ryoichi Saito, Tatsuhiko Tachibana
We previously reported that monoclonal antibodies (mAbs) with a high isoelectric point (pI) value tended to exhibit fast plasma clearance (CL) and large steady-state volume of distribution (Vdss) in mice. However, the positive correlation between pI, CL, and Vdss cannot be described by the reported physiologically based pharmacokinetic (PBPK) models, in which FcRn-mediated transcytosis of mAbs is set
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Roles of human cytochrome P450 3A4/5 in dexamethasone 6β-hydroxylation mediated by liver microsomes and humanized liver in chimeric mice metabolically suppressed with azamulin Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-03-06 Shotaro Uehara, Makiko Shimizu, Hiroshi Suemizu, Hiroshi Yamazaki
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Evaluation and prediction of oral drug absorption and bioequivalence with food-druginteraction Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-03-06 Yasuhiro Tsume
This article reviews the impacts on the in vivo prediction of oral bioavailability (BA) and bioequivalence (BE) based on Biopharmaceutical classification systems (BCS) by the food-drug interaction (food effect) and the gastrointestinal (GI) environmental change. Various in vitro and in silico predictive methodologies have been used to expect the BA and BE of the test oral formulation. Food intake changes
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A novel method for predicting the unbound valproic acid concentration Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-03-05 Masayuki Ishikawa, Masashi Uchida, Takahiro Asakawa, Shota Suzuki, Shingo Yamazaki, Yuki Shiko, Yohei Kawasaki, Takaaki Suzuki, Itsuko Ishii
In this study, we constructed a prediction formula for unbound valproic acid (VPA) concentration that was more accurate and widely applicable than previously reported formulae. A total of 136 datasets from 75 patients were analyzed retrospectively. The median of free fraction of VPA was 0.16 (interquartile range: 0.07; range: 0.07–0.45). The parameter that combined total VPA concentration (CtVPA) and
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Black ginger extract and its active compound, 5,7-dimethoxyflavone, increase intestinal drug absorption via efflux drug transporter inhibitions Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-02-28 Rattiporn Boonnop, Paranee Meetam, Lawan Siangjong, Patoomratana Tuchinda, Piyanut Thongphasuk, Sunhapas Soodvilai, Sirima Soodvilai
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Physiological effects of food ingredients on intestinal epithelial cell function Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-02-25 Hideo Satsu, Shimon Kimura, Yuki Hori
Understanding the physiological effects of food ingredients on bodily functions is crucial for the development of foods for specified health use (FoSHU) and functional foods. To investigate this, intestinal epithelial cells (IECs) have been widely studied as they are most frequently exposed to the highest concentrations of food ingredients. Among the various functions of IECs, in this review, we have
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Generation of Caco-2 cells with predictable metabolism by CYP3A4, UGT1A1 and CES using the PITCh system Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-02-18 Naoki Yamada, Ryosuke Negoro, Keita Watanabe, Takuya Fujita
Caco-2 cells are widely used as an in vitro intestinal model. However, the expression levels of the drug-metabolizing enzymes CYP3A4 and UGT1A1 are lower in these cells than in intestinal cells. Furthermore, the majority of prodrugs in use today are ester-containing, and carboxylesterase (CES) 1 and CES2 are among the enzymes that process the prodrugs into drugs. In the human small intestine, CES1
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Involvement of multiple cytochrome P450 isoenzymes in drug interactions between ritonavir and direct oral anticoagulants Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-02-18 Yuta Tamemoto, Yukihiro Shibata, Natsumi Hashimoto, Hiromi Sato, Akihiro Hisaka
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Population pharmacokinetics of duloxetine in Japanese pediatric patients with major depressive disorder Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-02-15 Risa Yokokawa Shibata, Ryuji Kubota, Kazunori Uenaka, Atsunori Kaibara, Toshihiro Wajima
The objectives of this analysis were to characterize the pharmacokinetics of duloxetine in Japanese pediatric patients aged 9–17 years with major depressive disorder (MDD) and to explore potential intrinsic factors affecting its pharmacokinetics. A population pharmacokinetic (PK) model was developed with plasma steady-state duloxetine concentrations from Japanese pediatric patients with MDD in an open-label
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Effect of antibiotic-administration period on hepatic bile acid profile and expression of pharmacokinetic-related proteins in mouse liver, kidney, and brain capillaries Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-02-09 Ryotaro Yagi, Takeshi Masuda, Shingo Ito, Sumio Ohtsuki
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Validation of a genotyping technique for a surrogate marker of HLA-B*58:01 for allopurinol-induced Stevens–Johnson syndrome and toxic epidermal necrolysis in the Japanese population Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-02-08 Eri Tsukagoshi, Ryosuke Nakamura, Yoichi Tanaka, Keiko Maekawa, Masahiro Hiratsuka, Hideo Asada, Yoshiro Saito
Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare but severe cutaneous adverse drug reactions. Certain human leukocyte antigen (HLA) types have been associated with SJS/TEN onset, e.g., HLA-B*58:01 with allopurinol-induced SJS/TEN, but HLA typing is time-consuming and expensive; thus, it is not commonly used in clinical situations. In the previous work, we demonstrated that
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Bioavailability of tetracyclines is substantially increased by administration of cyclosporine A, a non-specific efflux-pump blocker Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-02-04 Hubert Ziółkowski
Objectives To investigate how cyclosporine A, a nonspecific efflux-pump blocker, affects the plasma concentrations and oral bioavailability of tigecycline, oxytetracycline, chlortetracycline, doxycycline, minocycline, and tetracycline. Methods Broiler chickens were used as an animal model. The tetracyclines (10 mg/kg BW) were administered intravenously, orally, and orally with cyclosporine A (50 mg/kg
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Novel food drug interaction mechanism involving acyclovir, chitosan and endogenous mucus Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-01-24 Mauricio A. García, Gönül Hensler, Jozef Al-Gousous, Jonas Pielenhofer, Manfred Wagner, Hans Lennernäs, Peter Langguth
Drug absorption from drug products may be affected by pharmaceutical excipients and/or food additives through different mechanisms. Chitosan is a recognized nutraceutical, with potential as an excipient due to its permeability enhancer properties. While chitosan properties have been evaluated in in vitro and pre-clinical models, studies in humans are scarce. Unexpectedly, a controlled clinical trial
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Construction of a fused grid-based CYP2C8-Template system and the application Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-01-20 Yasushi Yamazoe, Yoshiya Yamamura, Kouichi Yoshinari
A ligand-accessible space in the CYP2C8 active site was reconstituted as a fused grid-based Template1 with the use of structural data of the ligands. An evaluation system of CYP2C8-mediated metabolism has been developed on Template with the introduction of the idea of Trigger-residue initiated ligand-movement and fastening. Reciprocal comparison of the data of simulation on Template with experimental
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A family study of compound variants of flavin-containing monooxygenase 3 (FMO3) in Japanese subjects found by urinary phenotyping for trimethylaminuria Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2023-01-09 Makiko Shimizu, Akane Yamamoto, Miaki Makiguchi, Erika Shimamura, Yuka Yokota, Mizuki Harano, Hiroshi Yamazaki
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Food effects on gastrointestinal physiology and drug absorption Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2022-12-20 Atsushi Kambayashi, Yoshiyuki Shirasaka
Food ingestion affects the oral absorption of many drugs in humans. In this review article, we summarize the physiological factors in the gastrointestinal (GI) tract that affect the in vivo performance of orally administered solid dosage forms in fasted and fed states in humans. In particular, we discuss the effects of food ingestion on fluid characteristics (pH, bile concentration, and volume) in
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Impact of P-glycoprotein on intracellular drug concentration in peripheral blood mononuclear cells and K562 cells Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2022-12-16 Kohei Ito, Marina Naoi, Kotaro Nishiyama, Takashi Kudo, Yasuhiro Tsuda, Caroline MacLean, Naoki Ishiguro
P-glycoprotein (P-gp) expression in lymphocytes is variable and 2-fold higher in rheumatoid arthritis (RA) patients with treatment resistance than in healthy subjects. To date the information on P-gp-mediated drug interaction in lymphocyte is limited. We analyzed the importance on P-gp in lymphocytes using peripheral blood mononuclear cells (PBMCs) together with K562, K562/Adr, and K562/Vin cells,
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High hepatic and plasma exposures of atorvastatin in subjects harboring impaired cytochrome P450 3A4*16 modeled after virtual administrations and possibly associated with statin intolerance found in the Japanese adverse drug event report database Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2022-12-07 Koichiro Adachi, Katsuhiro Ohyama, Yoichi Tanaka, Tasuku Sato, Norie Murayama, Makiko Shimizu, Yoshiro Saito, Hiroshi Yamazaki
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Constitutive androstane receptor-responsive elements for mouse Cyp1a2 transcriptional activation induced by constitutive androstane receptor ligands Drug Metab. Pharmacokinet. (IF 2.1) Pub Date : 2022-12-05 Yuki Kawasaki, Nobuo Nemoto, Tsutomu Sakuma