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Biopharmaceutics & Drug Disposition

Andy Pike, Neil J Flanagan, R Ian Storer, Nigel A Swain, Elaine Tseng
PF-06456384 is an extremely potent and selective blocker of the Nav 1.7 sodium channel designed as a potential intravenous (i.v.) analgesic targeting high potency and rapid clearance to minimize the potential for residual effects following the end of infusion. In our previous experience targeting oral molecules, the requirement to obtain potent, Nav 1.7 selective molecules led to a focus on acidic, amphipilic compounds cleared primarily by organic anion-transporting polypeptide mediated hepatic uptake and subsequent biliary excretion...
September 3, 2018: Biopharmaceutics & Drug Disposition
Stefan De Buck, Klaus Kucher, Hisanori Hara, Cathy Gray, Ralph Woessner
This study investigated the effect of itraconazole, a strong dual inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) on the single dose pharmacokinetics of leniolisib. In order to differentiate the specific contribution of CYP3A from P-gp, the potential interaction with quinidine, a strong inhibitor of P-gp but not CYP3A, was studied as well. Using a fixed-sequence, 3-way crossover design, twenty healthy male subjects received single oral doses of 10 mg leniolisib during 3 phases separated by a washout: (1) leniolisib alone, (2) 200 mg itraconazole once daily for 9 days plus leniolisib on day 5, and (3) 300 mg quinidine administered 1 hour before and 3 hours after leniolisib...
September 1, 2018: Biopharmaceutics & Drug Disposition
Hui Guo, Cuncai Wang, Zhen Liu, Huayong Gu, Yuwen Li, Li Zhao, Ranran Hou, Jiajia Zhu, Harvey Ho, Zhihui Hao
Although the study of bioequivalence waivers in humans is already well-established, their application and translation into animals, which are complicated by differences in physiology, have only recently become subjects of interest. The main purpose of this paper is to quantify the liquid volume affecting drug dissolution in pig stomachs. We used magnetic resonance imaging (MRI) to scan 18 Bama miniature pigs weighing 15, 30 or 50 kg. Amira 6.0.1 software was used for 3D image processing. We found that the gastric fluid volume had a linear relationship with the weight of pig (R2  = 0...
August 17, 2018: Biopharmaceutics & Drug Disposition
Bingfeng Luo, Jing Li, Tao Yang, Wenbin Li, Juanhong Zhang, Chang Wang, Anpeng Zhao, Rong Wang
With studies indicative of altered renal excretion under high altitude (HA)-induced hypobaric hypoxia (HH), consideration of better therapeutic approaches has continuously been aimed in research for HA related illness management. Pharmacokinetics of drugs like furosemide might be altered under hypoxic condition, which makes essential to establish different dose-regimen to maintain therapeutic efficacy or avoid toxic side effects at HA. Simultaneously, the drug-drug interactions (DDIs) mediated by OAT1 was occurred at HA, to severely affect furosemide pharmacokinetics...
August 17, 2018: Biopharmaceutics & Drug Disposition
Tomohide Uno, Ryosuke Nakano, Rina Kitagawa, Mai Okada, Kengo Kanamaru, Shinji Takenaka, Yuichi Uno, Hiromasa Imaishi
CYP2C9 is a human microsomal cytochrome P450c (CYP). Much variation in CYP2C9 levels and activity can be attributed to polymorphisms of this gene. Wild-type CYP2C9 and ten mutants were coexpressed with NADPH-cytochrome P450 reductase in Escherichia coli. The hydroxylase activities toward steroids were examined. CYP2C9.2, CYP2C9.3, CYP2C9.4, CYP2C9.16, CYP2C9.28, CYP2C9.48 and CYP2C9.52 had higher testosterone 6β-hydroxylation than CYP2C9.1. CYP2C9.4 showed higher progesterone 6β-hydroxylation activity than CYP2C9...
August 11, 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
Miguel Ángel Cabrera-Pérez, Hai Pham-The, Mirna Fernández Cervera, Rosario Hernández-Armengol, Claudia Miranda-Pérez de Alejo, Yudileidy Brito-Ferrer
The accuracy of the 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 have been analysed. The experimental models included the in situ rat intestinal perfusion, the ex vivo rat intestinal tissue in an Ussing chamber, the MDCK and Caco-2 cell monolayers, and the parallel artificial membrane (PAMPA). The theoretical models included the octanol-water partition coefficient and the QSPeR (Quantitative Structure-Permeability Relationship) model recently developed...
July 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 age-related changes in the expression and activity of seven hepatic drug metabolizing enzymes (DMEs) in male wild-type and breast cancer resistance protein knockout (Bcrp1-/- ) FVB mice. The protein expression of four cytochrome P450 (Cyps) (Cyp3a11, 2d22, 2e1, and 1a2), and 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 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 2018: Biopharmaceutics & Drug Disposition
Kaori Morimoto, Yuuta Tominaga, Yuta Agatsuma, 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 the progression of CKD. This study examined the 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 2018: Biopharmaceutics & Drug Disposition
Atsushi Kawase, Shunsuke Tateishi, Akira Kazaoka
Inflammatory conditions alter the expression and activity of factors influencing pharmacokinetics, such as metabolizing enzymes. The study 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 those in control rats...
June 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). Fluorescence spectrophotometry and high performance liquid chromatography verified the successful labelling of fucoidan by FITC. The results of the single-pass intestinal perfusion indicated that the jejunum and ileum are 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 the drugs (Papp ) A → B was 3...
June 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 studied widely, the acute pharmacokinetics (PK) and pharmacodynamics (PD) of curcumin in suppressing pro-inflammatory markers and epigenetic modulators remain unclear. This study evaluated the PK and PD of curcumin-induced suppression of lipopolysaccharide (LPS)-mediated inflammation in rat lymphocytes...
June 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. This study 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 with the ratios in samples from donors with heterozygous GA genotypes...
June 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...
June 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
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