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Biopharmaceutics & Drug Disposition

Miguel Ángel Cabrera-Pérez, Hai Pham-The, Mirna Fernández Cervera, Rosario Hernández-Armengol, Claudia Miranda-Pérez de Alejo, Yudileidy Brito-Ferrer
The accuracy of provisional estimation of the Biopharmaceutics Classification System (BCS) is heavily influenced by the permeability measurement. In this study, several theoretical and experimental models currently employed for BCS permeability classification has been analyzed. Experimental models included the in situ rat intestinal perfusion, the ex vivo rat intestinal tissue in Ussing chamber, the MDCK and Caco-2 cell monolayers, and the parallel artificial membrane (PAMPA). Theoretical models included octanol-water partition coefficients and QSPeR (Quantitative Structure-Permeability Relationship) models recently developed...
July 18, 2018: Biopharmaceutics & Drug Disposition
Haihui Zheng, Liping Wang, Sijing Zeng, Jiamei Chen, Haojia Wang, Jia Yu, Xia Gong, Huangyu Jiang, Xia Yang, Xiaoxiao Qi, Ying Wang, Linlin Lu, Ming Hu, Lijun Zhu, Zhongqiu Liu
This study aimed to reveal the age-related changes in expression and activity of seven hepatic drug metabolizing enzymes (DMEs) in male wild-type and breast cancer resistance protein knockout (Bcrp1-/- ) FVB mice. Protein expressions of four cytochrome P450 (Cyps) (Cyp3a11, 2d22, 2e1, and 1a2), three UDP-glucuronosyltransferases (Ugts) (Ugt1a1, 1a6a, and 1a9) in liver microsomes of wild-type and Bcrp1-/- FVB mice at different ages were determined using a validated ultra high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method...
July 17, 2018: Biopharmaceutics & Drug Disposition
Shuhei Fukuno, Katsuhito Nagai, Ayano Horii, Kohei Yamamoto, Hiroki Konishi
As there are to be known gender differences in the expression profiles of rat hepatic CYP2C, we examined the pharmacokinetic behavior of tolbutamide (TB), a typical probe for CYP2C, and hepatic enzyme activities for metabolizing TB in female rats to compare with male rats. On the pharmacokinetic analysis of TB after intravenous administration to female rats, the elimination rate constant at the terminal phase (ke ), total clearance (CLtot ) and the apparent volume of distribution at steady-state (Vdss ) were significantly lower than in male rats...
July 6, 2018: Biopharmaceutics & Drug Disposition
Yanming Xia, Ying Dong, Xiaoli Zhao, Liuqing Di, Junsong Li
Ursodeoxycholic acid (UDCA) is a first-line drug to treat intrahepatic cholestasis of pregnancy (ICP). However, its effects on the fetus are not clearly known. To better guide its clinical use, we aimed to study the mechanism underlying the placental transport of UDCA. The uptake and efflux of UDCA across placental apical membranes were studied using BeWo cells; effects of different exposure durations, UDCA concentrations, temperatures, and inhibitors of transporters were studied. A transwell assay was performed, and UDCA concentration in both fetal and maternal sides was measured using LC-MS/MS...
July 5, 2018: Biopharmaceutics & Drug Disposition
Kaori Morimoto, Yuuta Tominaga, Masanari Miyamoto, Shota Kashiwagura, Akira Takahashi, Yoshimi Sano, Kentaro Yano, Chihaya Kakinuma, Takuo Ogihara, Mikio Tomita
Indoxyl sulfate (IS) is a protein-bound uremic toxin that progressively accumulates in plasma during chronic kidney disease (CKD), and its accumulation is associated with progression of CKD. Here, we examined intestinal secretion of IS using in situ single-pass intestinal perfusion in a rat model of renal insufficiency, MRP2- and BCRP-overexpressing Sf9 membrane vesicles, and Caco-2 cell monolayers. An in situ single-pass perfusion study in CKD model rats demonstrated that a small amount of IS is secreted into intestinal lumen after iv administration of IS, and the clearance increased AUC-dependently...
July 5, 2018: Biopharmaceutics & Drug Disposition
Atsushi Kawase, Shunsuke Tateishi, Akira Kazaoka
Inflammatory conditions alter expression and activity of factors influencing pharmacokinetics, such as metabolizing enzymes. We examined alterations of hepatic protein levels of cytochrome P450 (CYP), UDP-glucuronosyltransferase (UGT) and nuclear receptors in rats with adjuvant-induced arthritis (AA rats), an inflammatory animal model, by liquid chromatography-tandem mass spectrometry-based targeted proteomics. The protein levels of CYP1A1, CYP1A2, CYP2A1, CYP2A3, CYP2C6, CYP2C12, CYP2D3, CYP2E1, CYP3A9, UGT1A1 and UGT1A2/3 in liver microsomes of AA rats were significantly lower than in those control rats...
June 30, 2018: Biopharmaceutics & Drug Disposition
E Zhang, Fulong Chu, Lixu Xu, Hao Liang, Shuliang Song, Aiguo Ji
A new method to label fucoidan sulfate was established with tyramine and fluorescein isothiocyanate isomer I (FITC). The fluorescence spectrophotometry and high performance liquid chromatography verified the successful labelling of fucoidan by FITC. The results of the single-pass intestinal perfusion indicated jejunum and ileum as the main absorption sites, and there was carrier saturation. In addition, fucoidan sulfate at 1 mg/mL had no inhibitory effect on Caco-2 cell proliferation. Studies on the transmembrane transport mechanism showed that fucoidan can be absorbed because the apparent permeability coefficient of drugs (Papp ) A→B was 3...
June 14, 2018: Biopharmaceutics & Drug Disposition
Sarandeep S S Boyanapalli, Ying Huang, Zhengyuan Su, David Cheng, Chengyue Zhang, Yue Guo, Rohit Rao, Ioannis P Androulakis, Ah-Ng Kong
Chronic inflammation is a key driver of cancer development. Nitrite levels, which are regulated by inducible nitric oxide synthase (iNOS), play a critical role in inflammation. While the anti-oxidant and anti-inflammatory effects of curcumin, a natural product present in the roots of Curcuma longa have been widely studied, the acute pharmacokinetics (PK) and pharmacodynamics (PD) of curcumin in suppressing pro-inflammatory markers and epigenetic modulators remain unclear. In this study, we evaluated the PK and PD of curcumin-induced suppression of lipopolysaccharide (LPS)-mediated inflammation in rat lymphocytes...
June 5, 2018: Biopharmaceutics & Drug Disposition
Adolfo Quiñones Lombraña, Nasi Li, Virginia Del Solar, G Ekin Atilla-Gokcumen, Javier G Blanco
Loxoprofen is an anti-inflammatory drug that requires bioactivation into the trans-OH metabolite to exert pharmacological activity. Evidence suggests that carbonyl reductase 1 (CBR1) is important during the bioactivation of loxoprofen. Here, we examined the impact of the functional single nucleotide polymorphism CBR1 rs9024 on the bioactivation of loxoprofen in a collection of human liver samples. The synthesis ratios of trans-OH loxoprofen/cis-OH loxoprofen were 33% higher in liver cytosols from donors homozygous for the CBR1 rs9024 G allele in comparison to the ratios in samples from donors with heterozygous GA genotypes...
May 31, 2018: Biopharmaceutics & Drug Disposition
Koji Kimura, Atsushi Yoshida, Risa Takayanagi, Yasuhiko Yamada
Adalimumab (ADA) is used as a therapeutic agent for Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has not been analysed theoretically. The present study analysed of sequential changes in the Crohn's disease activity index (CDAI) after repeated administrations of adalimumab using a pharmacokinetic and pharmacodynamic model. In addition, we analysed the validity of the dosage regimen, and the potential efficacy gained by increasing the dose and reducing the interval of administration...
May 23, 2018: Biopharmaceutics & Drug Disposition
Yuki Asai, Yukiko Sakakibara, Rina Inoue, Rikako Inoue, Masayuki Nadai, Miki Katoh
Single-walled carbon nanotubes (SWCNTs) are made from a rolled single sheet of graphene with a diameter in the nanometer range. SWCNTs are potential carriers for drug delivery systems because antibodies or drugs can be loaded on their surface; however, their effect on the activities of cytochrome P450 (CYP) remains unclear. The aim of this study was to investigate the effect of two kinds of SWCNTs with different lengths (FH-P- and SO-SWCNTs) on human CYP activity. In addition, other nano-sized carbon materials, such as carbon black, fullerene-C60 , and fullerene-C70 were also evaluated to compare their effects on CYP activities...
May 2018: Biopharmaceutics & Drug Disposition
Masato Hioki, Takuya Shimada, Tian Yuan, Takeo Nakanishi, Hidehiro Tajima, Maiko Yamazaki, Rina Yokono, Makiko Takabayashi, Kazuki Sawamoto, Gaku Akashita, Ken-Ichi Miyamoto, Tetsuo Ohta, Ikumi Tamai, Tsutomu Shimada, Yoshimichi Sai
Hepatic arterial infusion (HAI) chemotherapy is expected to be a more effective and safer method to treat the hepatic metastasis of pancreatic cancer than intravenous (iv) administration because of higher tumor exposure and lower systemic exposure. To clarify the uptake mechanism of nucleoside anticancer drugs, including gemcitabine (GEM), in pancreatic cancer, we investigated the uptakes of radiolabeled uridine (a general substrate of nucleoside transporters) and GEM in pancreatic cancer cell lines MIA-PaCa2 and As-PC1...
May 2018: Biopharmaceutics & Drug Disposition
Mysore S Anil Kumar, Kim Papp, Ryo Tainaka, Udaya Valluri, Xuegong Wang, Tong Zhu, Christian Schwabe
This study evaluated the pharmacokinetics (PK), efficacy, safety, and tolerability of bleselumab - a fully-human anti-CD40 monoclonal recombinant IgG4. Patients with moderate-to-severe psoriasis were randomized on day 1 to receive bleselumab or placebo on days 1, 15 and 29 in a dose-escalation of bleselumab at 0.1, 0.3, 1.0 or 3.0 mg/kg. The safety-analysis set (SAF) and full-analysis set (FAS) included all patients who received bleselumab or placebo, and the PK-analysis set (PKAS) included patients in the SAF with ≥1 quantifiable serum bleselumab concentration...
May 2018: Biopharmaceutics & Drug Disposition
Mastan Shaik, Shabana Shaik, Eswar Kumar Kilari
Gliclazide is a second-generation sulphonylurea drug widely used in the treatment of type 2 diabetes. However, there is no single report to describe the population pharmacokinetics of gliclazide in animal models. This study was aimed to evaluate the population pharmacokinetics (PK) of gliclazide in normal and alloxan-induced diabetic rabbits using nonlinear mixed effects modeling. A total of 90 New Zealand white rabbits were administered with three doses (4.13, 8.27 and 16.53 mg/kg b.wt) of gliclazide by an oral route...
May 2018: Biopharmaceutics & Drug Disposition
Kristin E Follman, Rutwij A Dave, Marilyn E Morris
Renal impairment (RI) significantly impacts the clearance of drugs through changes in the glomerular filtration rate, protein binding and alterations in the expression of renal drug transport proteins and hepatic metabolizing enzymes. The objectives of this study were to evaluate quantitatively the effects of renal impairment on the pharmacokinetics of drugs undergoing renal transporter-mediated reabsorption. A previously published semi-mechanistic kidney model incorporating physiologically relevant fluid reabsorption and transporter-mediated active renal reabsorption (PMID: 26341876) was utilized in this study...
April 2018: Biopharmaceutics & Drug Disposition
Shimul Halder, Aiko Tabata, Yoshiki Seto, Hideyuki Sato, Satomi Onoue
Carvedilol (CAR) belongs to biopharmaceutics classification system class-II drugs, with poor aqueous solubility and pH-dependent solubility. The present study aimed to develop a novel amorphous solid dispersion (ASD) of CAR with acidic counter ions for pH modifications in microenvironment to improve the pharmacokinetic properties under hypochlorhydric conditions. CAR-ASD was prepared by freeze-drying in combination with counter ions and hydroxypropyl cellulose, and their physicochemical properties including dissolution behavior, storage stability, and photostability were characterized...
April 2018: Biopharmaceutics & Drug Disposition
Holly P Quach, Tamara Dzekic, Paola Bukuroshi, K Sandy Pang
Vitamin D3 and the synthetic vitamin D analogs, 1α-hydroxyvitamin D3 [1α(OH)D3 ], 1α-hydroxyvitamin D2 [1α(OH)D2 ] and 25-hydroxyvitamin D3 [25(OH)D3 ] were appraised for their vitamin D receptor (VDR) associated-potencies as cholesterol lowering agents in mice in vivo. These precursors are activated in vivo: 1α(OH)D3 and 1α(OH)D2 are transformed by liver CYP2R1 and CYP27A1 to active VDR ligands, 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ] and 1α,25-dihydroxyvitamin D2 [1,25(OH)2 D2 ], respectively. 1α(OH)D2 may also be activated by CYP24A1 to 1α,24-dihydroxyvitamin D2 [1,24(OH)2 D2 ], another active VDR ligand...
April 2018: Biopharmaceutics & Drug Disposition
Boon Hooi Tan, Nafees Ahemad, Yan Pan, Uma Devi Palanisamy, Iekhsan Othman, Beow Chin Yiap, Chin Eng Ong
Many dietary supplements are promoted to patients with osteoarthritis (OA) including the three naturally derived compounds, glucosamine, chondroitin and diacerein. Despite their wide spread use, research on interaction of these antiarthritic compounds with human hepatic cytochrome P450 (CYP) enzymes is limited. This study aimed to examine the modulatory effects of these compounds on CYP2C9, a major CYP isoform, using in vitro biochemical assay and in silico models. Utilizing valsartan hydroxylase assay as probe, all forms of glucosamine and chondroitin exhibited IC50 values beyond 1000 μM, indicating very weak potential in inhibiting CYP2C9...
April 2018: Biopharmaceutics & Drug Disposition
Satoshi Koyama, Hiroshi Arakawa, Manabu Itoh, Norio Masuda, Kentaro Yano, Hajime Kojima, Takuo Ogihara
The NanoCulture Plate (NCP) is a novel microstructural plate designed as a base for the three-dimensional culture of cells/tissues. This study examined whether or not the metabolic capability of human primary hepatocytes is well maintained during culture on NCPs. The hepatocytes formed aggregates after seeding and their ATP content was well maintained during culture for 21 days. Expression of CYP1A2, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 mRNAs was detected throughout the 21-day culture period. Addition of CYP substrate drugs (midazolam, diclofenac, lamotrigine and acetaminophen) resulted in the formation of multiple metabolites with a corresponding decrease in the amounts of the unchanged compounds...
April 2018: Biopharmaceutics & Drug Disposition
Takuya Ebihara, Mitsuhiro Nishihara, Junzo Takahashi, Fumihiro Jinno, Yoshihiko Tagawa
In the search for orally available drugs, the prediction of human pharmacokinetics (PK) is essential for successfully selecting compounds that will be clinically useful. This report describes the selection of TAK-272 (SCO-272), a novel orally active renin inhibitor, as a clinical candidate via the detailed investigation of nonclinical PK data and human PK prediction. The bioavailability (BA) of TAK-272 after oral administration to rats and monkeys was low, especially in fasted monkeys, and the systemic exposure of TAK-272 was highly variable in monkeys...
March 2018: Biopharmaceutics & Drug Disposition
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