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Biopharmaceutics & Drug Disposition

Yuichi Uwai, Takato Suzuki, Ryota Kondo, Tatsuya Kawasaki, Tomohiro Nabekura
Lithium, administered to patients of bipolar disorders, is mainly excreted into urine, and the tubular reabsorption is involved. In this study, we characterized the renal excretion of lithium in rats subjected to renal ischemia for 60 minutes or 90 minutes. After intravenous injection of lithium chloride at 25 mg/kg, pharmacokinetic parameters of lithium were determined. In sham-operated rats, the renal clearance of lithium was calculated to be 1.49 ml/min/kg, and its ratio to creatinine clearance (fractional excretion) was 43...
November 4, 2018: Biopharmaceutics & Drug Disposition
Zhenxian Zhang, Phillip M Gerk
Phenylephrine (PE) has low and variable oral bioavailability in humans, due in part to presystemic metabolism by sulfation. LS180 cells were used as a model of the human intestinal epithelium to examine phenylephrine metabolism and its inhibition by GRAS and dietary compounds. Curcumin, zingerone, resveratrol, guaiacol, pterostilbene, and isoeugenol significantly inhibited PE disappearance, while vanillin, propylparaben, and eugenol did not. However, when propylparaben was combined with either vanillin or eugenol, PE disappearance was significantly inhibited...
October 28, 2018: Biopharmaceutics & Drug Disposition
Sangwoo Ryu, Jonathan Novak, Roshan Patel, Phillip Yates, Li Di
The effect of low temperature (4°C) on plasma protein binding and tissue binding was evaluated for the first time using a large set of structurally diverse compounds covering a wide range of physiochemical properties and fraction unbound values. These results show that temperature has little effect on plasma protein binding and tissue binding and that the measured binding values at 4°C are equivalent, on average, to those at physiological temperature (37°C). The exception is indomethacin, where binding component(s) changed during long incubation at 37°C...
October 25, 2018: Biopharmaceutics & Drug Disposition
Shu Yang, Jinping Hu, Yan Li, Zhigang Zhao
SYL-927, a novel and selective S1P1 agonist, is transferred to its active phosphate for regulation of lymphocytes recirculation. This in vitro metabolism study is to elucidate P450-mediated oxidation pathway of SYL-927 in human liver microsomes (HLMs). The results demonstrated that the ω-1 hydroxylated metabolite SYL-927-M was formed after incubation of SYL-927 with HLMs. Recombinant human CYP1A1 and CYP2J2 can efficiently catalyze SYL-927-M formation, followed by markedly less substrate conversion with CYP1A2, CYP2C19 and CYP2D6...
October 25, 2018: Biopharmaceutics & Drug Disposition
Yuan Chen, Rui Zhu, Fang Ma, Jialin Mao, Eugene C Chen, Edna Choo, Srikumar Sahasranaman, Lichuan Liu
GDC-0810 was under development as an oral anti-cancer drug for the treatment of estrogen receptor-positive breast cancer as a single agent or in combination. In vitro data indicated that GDC-0810 is a potent inhibitor of OATP1B1/1B3. To assess clinical risk, PBPK model was developed to predict the transporter drug-drug interaction (tDDI) between GDC-0810 and pravastatin in human. The PBPK model was constructed in Simcyp® by integrating in vitro and in vivo data for GDC-0810. The prediction of human pharmacokinetics (PK) was verified using GDC-0810 phase I clinical PK data...
October 18, 2018: Biopharmaceutics & Drug Disposition
Liping Li, Hongmei Lei, Wei Wang, Weijuan Du, Jingqun Yuan, Meijuan Tu, Hui Zhou, Su Zeng, Huidi Jiang
Nuciferine (NF), one of the main and effective components in Nelumbo nucifera Gaertn. leaf extracts, is a promising drug candidate for the treatment of obesity-related diseases, while metformin is a first line therapeutic drug for type 2 diabetes mellitus. Since nuciferine and metformin are likely to be co-administered, the aim of the present study was to evaluate whether co-administration of nuciferine would influence the liver (target tissue) distribution and the anti-diabetic effect of metformin by inhibiting hepatic organic cation transporter 1 (OCT1) and multidrug and toxin extrusion 1 (MATE1)...
October 7, 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
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 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...
September 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-induced hypobaric hypoxia, the consideration of better therapeutic approaches has long been the aim of research on the management of high altitude related illness. The pharmacokinetics of drugs such as furosemide might be altered under hypoxic conditions, making it essential to establish different dose-regimens to maintain therapeutic efficacy or to avoid toxic side effects at high altitude. Simultaneously, drug-drug interactions (DDIs) mediated by OAT1 occur at high altitude, severely affecting furosemide pharmacokinetics...
September 2018: Biopharmaceutics & Drug Disposition
Tomohide Uno, Ryosuke Nakano, Risa 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 co-expressed 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...
September 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
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 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
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