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Biopharmaceutics & Drug Disposition

Xiaohui Zeng, Dake Cai, Qiaohuang Zeng, Zhao Chen, Guoping Zhong, Juncheng Zhuo, Haining Gan, Xuejun Huang, Ziming Zhao, Nan Yao, Dane Huang, Chengzhe Zhang, Dongmei Sun, Yuxing Chen
Curcumin (CUR) is known to exert numerous health-promoting effects in pharmacological studies, but its low-bioavailability hinders the development of CUR as a feasible therapeutic agent. Piperine (PIP) has been reported to enhance the bioavailability of CUR, but the underlying mechanism remains poorly understood. In an attempt to find the mechanism by which PIP enhances the bioavailability of CUR, dosage ratio (CUR: PIP) and PIP pre-treatment are hypothesized as key factors for bioavailability improvement in this combination...
November 23, 2016: Biopharmaceutics & Drug Disposition
Ming Li, Inge A M de Graaf, Marina H de Jager, Geny M M Groothuis
Although intestinal P-glycoprotein (P-gp) has been extensively studied in vitro and in animals, its activity and the consequences of P-gp inhibition for drug disposition and toxicity in humans are still difficult to accurately extrapolate from these studies. Moreover, existing in vitro models do not take into consideration that the intestine is heterogeneous with respect to P-gp expression. Recently, we reported rat precision-cut intestinal slices (PCIS) as a physiological ex vivo model to study the regional gradient of P-gp activity and inhibition...
October 19, 2016: Biopharmaceutics & Drug Disposition
Kazumi Mori, Ryuta Saito, Yoshinobu Nakamaru, Makiko Shimizu, Hiroshi Yamazaki
Canagliflozin is a recently developed sodium-glucose cotransporter (SGLT) 2 inhibitor that promotes renal glucose excretion and is considered to inhibit renal SGLT2 from the luminal side of proximal tubules. Canagliflozin reportedly inhibits SGLT1 weakly and suppresses postprandial plasma glucose, suggesting that it also inhibits intestinal SGLT1. However, it is difficult to measure the drug concentrations of these assumed sites of action directly. The pharmacokinetic-pharmacodynamic (PK/PD) relationships of canagliflozin remain poorly characterized...
September 7, 2016: Biopharmaceutics & Drug Disposition
Tsuyoshi Takahashi, Tatsuyuki Ohtsuka, Yasuhiro Uno, Masahiro Utoh, Hiroshi Yamazaki, Toshiyuki Kume
Cyclosporine A, an inhibitor of hepatic organic anion transporting polypeptides (OATPs), reportedly increased plasma concentrations of probe substrates, although its maximum unbound blood concentrations were lower than the experimental half-maximal inhibitory (IC50 ) concentrations. Pre-incubation with cyclosporine A in vitro before simultaneous incubation with probes has been reported to potentiate its inhibitory effects on recombinant human OATP-mediated probe uptake. In the present study, the effects of cyclosporine A and rifampicin on recombinant cynomolgus monkey OATP-mediated pitavastatin uptake were investigated in pre- and simultaneous incubation systems...
September 7, 2016: Biopharmaceutics & Drug Disposition
Shin-Ichi Inaba, Maki Goto, Kaoru Tanaka-Takanaka, Hisako Tanaka, Wataru Tomisato, Hiroshi Yuita, Hiromi Doi-Komuro, Ryotaku Inoue, Keiko Oshima, Takashi Kagari, Takaichi Shimozato, Takashi Izumi
Pharmacokinetic (PK) and pharmacodynamic (PD) modeling was conducted for the reduction of peripheral lymphocytes after oral administration of CS-0777 to healthy rats, monkeys and experimental autoimmune encephalomyelitis (EAE) induced rats. The phosphorylated active metabolite of CS-0777, M1, is a selective sphingosine 1-phosphate receptor-1 modulator. A linear one- and two-compartment model with a reversible metabolism process characterized the time courses of CS-0777 and M1 concentrations in rats and monkeys, respectively...
December 2016: Biopharmaceutics & Drug Disposition
Jamie N Connarn, Ruijuan Luo, Jim Windak, Xinyuan Zhang, Andrew Babiskin, Marisa Kelly, Gloria Harrington, Vicki L Ellingrod, Masoud Kamali, Melvin McInnis, Duxin Sun
Bupropion and its three active metabolites exhibit clinical efficacy in the treatment of major depression, seasonal depression and smoking cessation. The pharmacokinetics of bupropion in humans is highly variable. It is not known if there are any non-reported metabolites formed in humans in addition to the three known active metabolites. This paper reports newly identified and non-reported metabolites of bupropion in human plasma samples. Human subjects were dosed with a single oral dose of 75 mg of an immediate release bupropion HCl tablet...
December 2016: Biopharmaceutics & Drug Disposition
Rajesh Krishna, Lilly East, Patrick Larson, Tara Siringhaus, Lisa Herpok, Crystal Bethel-Brown, Helen Manthos, John Brejda, Michael Gartner
Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once daily regimen (QD) at a dose of 1200 mg (2 x 600 mg) is under development and offers a new treatment option for HIV-1 infected treatment-naive subjects. Since raltegravir is eliminated mainly by metabolism via an UDP-glucuronosyltransferase (UGT) 1 A1-mediated glucuronidation pathway, co-administration of UGT1A1 inducers may alter plasma levels of raltegravir...
December 2016: Biopharmaceutics & Drug Disposition
Rajesh Krishna, Lilly East, Patrick Larson, Chandni Valiathan, Kathleen Deschamps, Julie Ann Luk, Crystal Bethel-Brown, Helen Manthos, John Brejda, Michael Gartner
Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice-daily (b.i.d.). Raltegravir 1200 mg once-daily (q.d.) (investigational q.d. formulation of 2 × 600 mg tablets; q.d. RAL) was found to be generally well tolerated and non-inferior to the marketed 400 mg b.i.d. dose at 48 weeks in a phase 3 trial. Since raltegravir is eliminated mainly by metabolism via a uridine diphosphate glucuronosyltransferase (UGT) 1A1-mediated glucuronidation pathway, co-administration of UGT1A1 inhibitors may increase the plasma levels of q...
December 2016: Biopharmaceutics & Drug Disposition
Shoji Kawauchi, Tsutomu Nakamura, Sayo Horibe, Toshihito Tanahashi, Shigeto Mizuno, Tsuneo Hamaguchi, Yoshiyuki Rikitake
The liver and the small intestine are closely related in the processes of drug absorption, metabolism and excretion via the enterohepatic circulation. Small intestinal ulcers are a serious adverse effect commonly occurring in patients taking nonsteroidal anti-inflammatory drugs. However, the influence of small intestinal ulcers on drug metabolism has not been established. This study examined the expressional changes of cytochrome P450 (CYP) in the liver using an indomethacin-induced small intestinal ulcer rat model and in cultured cells...
December 2016: Biopharmaceutics & Drug Disposition
Yan-Rong Ma, A-Xi Shi, Hong-Yan Qin, Tiffany Zhang, Yan-Fang Wu, Guo-Qiang Zhang, Xin-An Wu
Drug interactions are one of the commonest causes of side effects, particularly in long-term therapy. The aim of the current study was to investigate the possible effects of metoprolol on the pharmacokinetics of metformin in rats and to clarify the mechanism of drug interaction. In this study, rats were treated with metformin alone or in combination with metoprolol. Plasma, urine and tissue concentrations of metformin were determined by HPLC. Western blotting and real-time qPCR were used to evaluate the expression of rOCTs and rMATE1...
December 2016: Biopharmaceutics & Drug Disposition
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November 2016: Biopharmaceutics & Drug Disposition
Rong Shi, Jiasheng Wu, Cong Meng, Bingliang Ma, Tianming Wang, Yuanyuan Li, Yueming Ma
The db/db mouse is one of the most popular animal models for type 2 diabetes mellitus, but changes in the activities of important P450s and UGTs are still not completely clear. This study was designed to investigate the alterations of major hepatic cytochrome P450s and UDP-glucuronyltransferase enzymes in db/db mice. Mouse liver microsomes (MLMs) were obtained from male db/db mice and their wild type littermates. After incubation of the substrates separately with MLMs, the samples were pooled and analysed by high-throughput liquid chromatography-tandem mass spectrometry system for the simultaneous study of nine phase I metabolic reactions and three glucuronidation conjugation reactions to determine the activity of the metabolic enzymes...
October 2016: Biopharmaceutics & Drug Disposition
Xingdong Wang, Zhi Rao, Hongyan Qin, Guoqiang Zhang, Yanrong Ma, Yongwen Jin, Miao Han, Axi Shi, Yanping Wang, Xinan Wu
The usage of irinotecan hydrochloride (CPT-11) chemotherapy is hindered by its dose-limiting diarrhea which appears to be associated with the intestinal exposure to SN-38, the active metabolite of CPT-11. Hesperidin, a safe and natural food ingredient flavonoid, exhibits various biological properties. Accumulated evidence showed that the regulatory effect of hesperidin on the expression of Mrp2 in the liver may be one of the critical factors controlling the biliary excretion of SN-38. This study examined the effect of hesperidin on the pharmacokinetics of CPT-11 and SN-38 as well as the regulatory effect on the hepatic expression of Mrp2...
October 2016: Biopharmaceutics & Drug Disposition
Krithika A Shetty, Matthew P Kosloski, Donald E Mager, Sathy V Balu-Iyer
The development of inhibitory antibodies against factor VIII (FVIII) is a major challenge in hemophilia A (HA) therapy. Such antibodies develop in nearly 30% of patients receiving replacement FVIII, abrogating therapeutic efficacy. This work evaluated whether B-domain deleted FVIII encapsulated in phosphatidylinositol containing lipid nanoparticles (PI-BDD FVIII) could serve as an efficacious FVIII replacement therapy in the presence of inhibitors. The HA mice were given clinically relevant doses of FVIII to develop inhibitors...
October 2016: Biopharmaceutics & Drug Disposition
Kazuhide Iwasaki, Yusuke Kitsugi, Kanami Ikeda, Takahiro Yoshikawa, Shinya Hosaka, Shotaro Uehara, Yasuhiro Uno, Masahiro Utoh, Hiroshi Yamazaki
Cynomolgus monkeys are used frequently in preclinical studies for new drug development due to their evolutionary closeness to humans. An antiretroviral drug, efavirenz, is a typical probe substrate for human cytochrome P450 (P450) 2B6, but is mainly metabolized by cynomolgus monkey P450 2C9. In this study, plasma concentrations of efavirenz were assessed in six cynomolgus monkeys genotyped for P450 2C9 c.334 A > C (I112L) (three wild-type, one heterozygote and two homozygotes) by high performance liquid chromatography with tandem mass spectrometry...
September 2016: Biopharmaceutics & Drug Disposition
Ayahisa Watanabe, Kei Mayumi, Kyohei Nishimura, Hiromi Osaki
1-Aminobenzotriazole (ABT) is a well-known in vivo nonspecific inhibitor of cytochrome P450 (CYP) enzymes. An effective dosing regimen of ABT for a multiple-administration study is needed to conduct pharmacological studies for proof-of-concept, although it has been established for single-administration study, to characterize the pharmacokinetics of drug candidates. This study demonstrated a suitable dosing vehicle of ABT for continuous administration and increased exposure to antipyrine, which is a nonspecific probe of CYP, using ABT for a long period in mice...
September 2016: Biopharmaceutics & Drug Disposition
Eunyoung Lee, Jong Cheol Shon, Kwang-Hyeon Liu
Cytochrome P450 (P450) 3A (CYP3A) is an enzyme responsible for the metabolism of therapeutic drugs such as midazolam, nifedipine, testosterone and triazolam. It is involved in 40% of all cases of P450-mediated metabolism of marketed drugs. Therefore, it is important to evaluate the CYP3A-mediated drug interaction potential of new chemical entities (NCEs). In the past, one P450 isoform-specific probe substrate has been used at a time to evaluate the degree of inhibition of P450 isoforms by using liquid chromatography-tandem mass spectrometry (LC-MS/MS)...
September 2016: Biopharmaceutics & Drug Disposition
Mi Hye Kwon, Ji Na Yoon, Yu Jin Baek, Yu Chul Kim, Yong Yeon Cho, Hee Eun Kang
Hepatic multidrug resistance-associated protein 2 (Mrp2) is responsible for the majority of the biliary elimination of endogenous and exogenous substances, therefore it is important to evaluate possible functional changes in Mrp2 activity under conditions of hyperlipidemia (HL). Thus, the present study assessed the protein expression and transporting activity of hepatic Mrp2 based on the in vivo biliary excretion of phenolsulfonphthalein (PSP) as a model anionic substrate for Mrp2 in poloxamer 407-induced hyperlipidemic rats (HL rats) and compared these values with those for control rats...
September 2016: Biopharmaceutics & Drug Disposition
Yousef A Bin Jardan, Dion R Brocks
The objectives of the current study were to characterize the pharmacokinetic profile of dronedarone in the rat, and to examine the effect of hyperlipidemia on its pharmacokinetics. Single doses of dronedarone were administered to rats intravenously (4 mg/kg), orally (55 mg/kg) and intraperitoneally (65 mg/kg). To induce hyperlipidemia, some of the rats were administered intraperitoneal doses of poloxamer 407 before giving an oral dose of dronedarone. After intravenous doses of 4 mg/kg dronedarone, plasma clearance and volume of distribution at steady-state were 25...
September 2016: Biopharmaceutics & Drug Disposition
Christopher J Endres, Aaron M Moss, Kazuya Ishida, Rajgopal Govindarajan, Jashvant D Unadkat
Ribavirin is used for the treatment of hepatitis C virus (HCV) infection. The equilibrative nucleoside transporter 1 (ENT1) expressed in hepatocytes transports ribavirin into the liver, the site of efficacy of the drug. However, it is still unclear whether ENT1 plays a dominant role in the hepatic distribution of the drug in vivo. In addition, due to fetal toxicity, administration of ribavirin to pregnant women with HCV infection is contraindicated. ENT1 might play a role in the fetal distribution and therefore the fetal toxicity of ribavirin...
September 2016: Biopharmaceutics & Drug Disposition
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