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Biopharmaceutics & Drug Disposition

Pil Joung Cho, Ju-Hyun Kim, Hye Suk Lee, Jeong Ah Kim, Sangkyu Lee
Licoricidin is a major prenylated isoflavone of Glycyrrhiza uralensis Fisch. (Leguminosae), and its pharmacological effects have been reported frequently. Typically, flavonoids having multiple hydroxyl groups are unambiguous substrates for glucuronyl conjugation by UDP-glucuronosyltransferases (UGTs). The pharmacological effects of flavonoids are derived from the conjugation of glucuronide to yield the bioactive metabolite. Here, we investigated the metabolism of licoricidin in pooled human liver microsomes (HLMs) using high-resolution quadrupole-orbitrap mass spectrometry...
January 12, 2019: Biopharmaceutics & Drug Disposition
Biljana Gatarić, Jelena Parojčić
Solubility and permeability are recognized as key parameters governing drug intestinal absorption and represent the basis for biopharmaceutics drug classification. The Biopharmaceutics Classification System (BCS) is widely accepted and adopted by regulatory agencies. However, currently established low/high permeability and solubility boundaries are subject of the ongoing scientific discussion. The aim of the present study is to apply data mining analysis on the selected drugs data set in order to develop human permeability predictive model based on selected molecular descriptors, and perform data clustering and classification to identify drug subclasses with respect to dose/solubility ratio (D/S) and effective permeability (Peff )...
January 11, 2019: Biopharmaceutics & Drug Disposition
Shinji Kobuchi, Mako Akutagawa, Yukako Ito, Toshiyuki Sakaeda
Capecitabine is a 5-fluorouracil (5-FU) derivative that is widely used in the treatment of colorectal cancer. The plasma ratio of dihydrouracil (UH2 ) to uracil (Ura) is expected to gain relevance as an indirect-response biomarker to estimate the activity of dihydropyrimidine dehydrogenase (DPD). The latter is a rate-limiting enzyme in the catabolism of 5-FU in the capecitabine-based regimen. However, the relationship between the pharmacokinetics of capecitabine and the plasma UH2 /Ura ratio is still unknown...
December 28, 2018: Biopharmaceutics & Drug Disposition
Ikumi Washio, Takeo Nakanishi, Naoki Ishiguro, Bojan Bister, Ikumi Tamai
P-glycoprotein (P-gp, multidrug resistance 1 (MDR1)) overexpression confers multidrug resistance to cancer cells, and P-gp in cell lines transfected with MDR1 or selected with chemotherapeutics significantly affect the anticancer drug efficacy. Although human cancer cell line panels consisting of defined tumor cell lines expressing endogenous P-gp have been used to screen drugs in pharmaceutical industries, endogenous P-gp affecting in vitro anticancer drug efficacy is unclear. We assessed the impact of P-gp expression on anticancer drug efficacy by using five colon cancer cell lines expressing varying endogenous P-gp levels and by selecting from the Cancer Cell Line Encyclopedia (CCLE)...
December 16, 2018: Biopharmaceutics & Drug Disposition
Neha Maharao, Jurgen Venitz, Phillip M Gerk
The present study evaluated the potential of five generally recognized as safe (GRAS) or dietary compounds (α-mangostin, chrysin, ginger extract, pterostilbene and silybin) to inhibit oxidative (CYP) and conjugative (UGT) metabolism using pooled human intestinal and liver microsomes. Buprenorphine was chosen as the model substrate as it is extensively metabolized by CYPs to norbuprenorphine and by UGTs to buprenorphine glucuronide. Chrysin, ginger extract, α-mangostin, pterostilbene and silybin were tested for their inhibition of formation of norbuprenorphine or buprenorphine glucuronide in both intestinal and liver microsomes...
December 5, 2018: Biopharmaceutics & Drug Disposition
Shin-Ichiro Ogawa, Yoshihiko Tunenari, Hiroyuki Kawai, Hiroshi Yamazaki
The metabolic profiles and pharmacokinetics of pemafibrate, a novel selective peroxisome proliferator activated receptor-alpha modulator currently launched as an antidyslipidemic drug, were investigated in vitro using hepatocytes from rats, monkeys, and humans and in vivo in rats and monkeys. Hepatocytes from rats, monkeys, and humans all biotransformed pemafibrate to its demethylated form (M1). The bioavailabilities of pemafibrate in Sprague-Dawley rats and cynomolgus monkeys were 15% and 87%, respectively, after a single oral administration of pemafibrate (1 mg/kg)...
December 5, 2018: Biopharmaceutics & Drug Disposition
Guoqiang Zhang, Yanrong Ma, Dali Xi, Zhi Rao, Xiaohan Sun, Xin An Wu
Metformin is always used the baseline antidiabetic therapy of patients with type 2 diabetes mellitus (T2DM) and hyperuricemia. Metformin excreted into urine through active secretion mediated by rOCTs and rMATE1.The aim of this study was to identify the effects of high uric acid on the disposition and its mechanism. In vivo study, hyperuricemic animal model was induced by intraperitoneal injection of potassium oxonate (250 mg/kg) in rats. Metformin (100mg/kg) was administered orally to investigate the pharmacokinetics in control and hyperuricemic rats, respectively...
November 28, 2018: Biopharmaceutics & Drug Disposition
Yuichi Uwai, Takato Suzuki, Ryota Kondo, Tatsuya Kawasaki, Tomohiro Nabekura
Lithium, administered to patients with bipolar disorders, is mainly excreted in the urine, and tubular reabsorption is involved. This study characterized the renal excretion of lithium in rats subjected to renal ischemia for 60 min or 90 min. After intravenous injection of lithium chloride at 25 mg/kg, the 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 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 generally recognized as safe (GRAS) and dietary compounds. Curcumin, zingerone, resveratrol, guaiacol, pterostilbene and isoeugenol significantly inhibited phenylephrine disappearance, while vanillin, propylparaben and eugenol did not. However, when propylparaben was combined with either vanillin or eugenol, the phenylephrine disappearance was significantly inhibited...
November 2018: Biopharmaceutics & Drug Disposition
Sangwoo Ryu, Jonathan J 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...
November 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 the regulation of lymphocyte recirculation. This in vitro metabolism study is to elucidate the 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 catalyse SYL-927-M formation, followed by markedly less substrate conversion with CYP1A2, CYP2C19 and CYP2D6...
November 2018: Biopharmaceutics & Drug Disposition
Yuan Chen, Rui Zhu, Fang Ma, Jialin Mao, Eugene C Chen, Edna F 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, a 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...
November 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)...
November 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
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...
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
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