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Drug Metabolism and Pharmacokinetics

Zhe Zhang, Guo Ma, Caifu Xue, Hong Sun, Ziteng Wang, Xiaoqiang Xiang, Weimin Cai
Studies on the efficacy evaluation of UDP-glucuronosyltransferases (UGTs) substrates often ignore the existence of active metabolites. However, the present study aims to establish an in-vitro Phase II metabolism system to predict their pharmacological effects after metabolism. Rat liver microsomes (RLMs) encapsulated in a F127'-Acr-Bis (FAB) hydrogel were placed in the incubation system. Baicalein (BA) was chosen as a model drug and the metabolic activity was investigated by quantitating the metabolite Baicalin (BG)...
January 30, 2019: Drug Metabolism and Pharmacokinetics
Kaori Yasuda, Kairi Okamoto, Sera Ueno, Kasumi Itoh, Miyu Nishikawa, Shinichi Ikushiro, Toshiyuki Sakaki
Sesamin is known to have various biological effects. Although several metabolites of sesamin have been identified, its metabolism by phase II enzymes remains unclear, because usually its sulfo- and glucurono-conjugates in plasma and urine are analyzed after sulfatase/β-glucuronidase treatment. In this study, the metabolites of sesamin in rats administrated with sesamin (100 mg/kg b.w.) were analyzed without sulfatase/β-glucuronidase treatment. Two sulfate conjugates of sesamin monocatechol (SC-1) were detected in the liver and plasma...
December 31, 2018: Drug Metabolism and Pharmacokinetics
Ryosuke Watari, Akihiro Matsuda, Shuichi Ohnishi, Hiroshi Hasegawa
Naldemedine tosylate, a peripherally acting μ-opioid receptor antagonist, is indicated for treatment of opioid induced constipation in both Japan and US. Naldemedine has limited ability to affect the central analgesic effect of opioid analgesics. In this study, we investigated the contribution of P-glycoprotein (P-gp) on the brain distribution of naldemedine. Naldemedine tosylate showed acceptable oral absorption in rats. Following a single oral administration of [14 C]-naldemedine tosylate to rats and ferrets, little radioactivity was detected in the region protected by the blood-brain barrier (BBB)...
December 23, 2018: Drug Metabolism and Pharmacokinetics
Kimiyoshi Ichidaa
No abstract text is available yet for this article.
December 15, 2018: Drug Metabolism and Pharmacokinetics
Chiyo K Imamura
Monoclonal antibodies (mAbs) have dramatically improved clinical outcomes for inflammatory and malignant diseases. The elimination route of mAbs is cellular uptake by nonspecific pinocytosis or receptor-mediated endocytosis followed by proteolytic degradation which is protected by neonatal Fc-receptor or mediated by antigenic target. There is a wide-interindividual variability in mAbs exposure due to target burden and other factors affecting unique their pharmacokinetics. It has been reported that higher exposures are correlated with better clinical outcomes of various therapeutic mAbs...
December 7, 2018: Drug Metabolism and Pharmacokinetics
Akiko Ishii-Watabe, Takashi Kuwabara
The concept of biosimilar was established in the early 2000s in EU. Currently, the regulatory framework for biosimilar has also been established in the US, Japan, and other countries. As of 2018, biosimilars for infliximab, adalimumab, rituximab, trastuzumab, and bevacizumab have been approved. During the development of a biosimilar, product quality should be evaluated and compared with those of the reference product extensively. Among the quality attributes of therapeutic antibodies, FcRn binding and related structures are well known to affect the pharmacokinetic profile of the product...
December 7, 2018: Drug Metabolism and Pharmacokinetics
(no author information available yet)
No abstract text is available yet for this article.
February 2019: Drug Metabolism and Pharmacokinetics
Tatsuhiko Tachibana, Takashi Kuwabara
No abstract text is available yet for this article.
February 2019: Drug Metabolism and Pharmacokinetics
Brandon Bumbaca, Zhe Li, Dhaval K Shah
Protein and peptide conjugates have become an important component of therapeutic and diagnostic medicine. These conjugates are primarily designed to improve pharmacokinetics (PK) of those therapeutic or imaging agents, which do not possess optimal disposition characteristics. In this review we have summarized preclinical and clinical PK of diverse protein and peptide conjugates, and have showcased how different conjugation approaches are used to obtain the desired PK. We have classified the conjugates into peptide conjugates, non-targeted protein conjugates, and targeted protein conjugates, and have highlighted diagnostic and therapeutic applications of these conjugates...
November 22, 2018: Drug Metabolism and Pharmacokinetics
Patrick M Glassman, Joseph P Balthasar
Over the past few decades, monoclonal antibodies (mAbs) have become one of the most important and fastest growing classes of therapeutic molecules, with applications in a wide variety of disease areas. As such, understanding of the determinants of mAb pharmacokinetic (PK) processes (absorption, distribution, metabolism, and elimination) is crucial in developing safe and efficacious therapeutics. In the present review, we discuss the use of physiologically-based pharmacokinetic (PBPK) models as an approach to characterize the in vivo behavior of mAbs, in the context of the key PK processes that should be considered in these models...
November 22, 2018: Drug Metabolism and Pharmacokinetics
Kazuaki Sugio, Daisei Inoda, Masayuki Masuda, Isao Azumaya, Shotaro Sasaki, Kazumi Shimono, Vadivel Ganapathy, Seiji Miyauchi
Using X. laevis oocyte expression system, we investigated whether human Na+ -coupled monocarboxylate transporter 1 (SLC5A8, hSMCT1) is involved in 2,4-dichlorophenoxyacetate (2,4-D) uptake by the renal tubular epithelial cells. 2,4-D is a herbicide that causes nephrotoxicity. Heterologous expression of hSMCT1 in X. laevis oocytes conferred the ability to take up 2,4-D; the induced uptake process was Na+ -dependent and electrogenic. The Na+ -dependent uptake of 2,4-D was inhibited not only by known hSMCT1 substrates, but also by many structural analogs of 2,4-D...
November 8, 2018: Drug Metabolism and Pharmacokinetics
Kenta Haraya, Tatsuhiko Tachibana, Tomoyuki Igawa
Monoclonal antibodies (mAbs) have become an important therapeutic option for several diseases. Since several mAbs have shown promising efficacy in clinic, the competition to develop mAbs has become severe. In efforts to gain a competitive advantage over other mAbs and provide significant benefits to patients, innovations in antibody engineering have aimed at improving the pharmacokinetic properties of mAbs. Because engineering can provide therapeutics that are more convenient, safer, and more efficacious for patients in several disease areas, it is an attractive approach to provide significant benefits to patients...
November 1, 2018: Drug Metabolism and Pharmacokinetics
Noriko Iwamoto, Takashi Shimada
In recent studies, the development of bioanalysis technologies using liquid chromatography-tandem mass spectrometry (LC-MS/MS) has attracted attention. Our developed nano-surface and molecular-orientation limited (nSMOL) proteolysis enables Fab-specific proteolysis and is optimal for LC-MS/MS analysis of antibody drugs and Fc-fusion proteins in biological samples. In this nSMOL method, antibodies and Fc-fusion proteins are held in pores of the particle and the subsequent proteolysis is carried out with protease-immobilized nanoparticles...
October 19, 2018: Drug Metabolism and Pharmacokinetics
Yasushi Yamazoe, Takahiro Goto, Masahiro Tohkin
A hexagonal-grid based template system has been developed to a predicting tool of CYP3A4-mediated reactions through the reconstitution of the active site with the assembly of the ligands. Simultaneous interactions of flattened-shape ligands at two sites of CYP3A4, oxidizing- and triggering-sites, are essential ideas, which were supported in the simulation results of various ligands on the template. The interactions were accomplished with either uni-molecule bindings or bi-molecule bindings with ligands termed pro-metabolized and trigger molecules...
October 15, 2018: Drug Metabolism and Pharmacokinetics
Shawn A Means, Harvey Ho
The metabolism zonation in liver lobules is well known yet its incorporation into the mathematical models of acetaminophen (APAP) metabolism is still primitive - only the oxidation pathway via reaction with the cytochrome P450 (CYP450) has been considered, yet the zonal heterogeneity exhibits in all three pathways including sulphation, glucuronidation and oxidation. In this paper we present a novel computational method where an intracellular APAP metabolism model is integrated into a Finite Element Model (FEM) of sinusoids, and the zonal heterogeneity in three metabolism pathways are all incorporated...
October 8, 2018: Drug Metabolism and Pharmacokinetics
Keisuke Oda, Nobuhiro Mori, Masayoshi Okumi, Miyuki Furusawa, Masashi Ishiguro, Kazuyuki Inoue, Satoshi Shuto, Kohei Unagami, Hideki Ishida, Kazunari Tanabe, Teruo Murakami
The cellular uptake of mizoribine (MZR), an immunosuppressant, and metabolism of MZR to MZR-5'- monophosphate (MZRP), an active metabolite, were evaluated in L5178Y-R mouse lymphoma cells and peripheral blood mononuclear cells (PBMCs) of rats and kidney transplant recipients (KTRs, n = 22). Real-time PCR analysis revealed the expression of ENT1 and ENT2 mRNAs, but not of CNTs, in L5178Y-R cells and rat's PBMCs. In L5178Y-R cells, the uptake of MZR was suppressed by adenosine, a substrate for ENT1 and ENT2, but not by 5-(4-nitrobenzyl)-6-thioinosine (0...
October 2018: Drug Metabolism and Pharmacokinetics
Y Amy Siu, Ming-Hong Hao, Vaishali Dixit, W George Lai
Celecoxib was characterized as a substrate of human cytochrome P450 (CYP) 2D6 in vitro. In recombinant CYP2D6, celecoxib hydroxylation showed atypical substrate inhibition kinetics with apparent Km , Ki , and Vmax of 67.2 μM, 12.6 μM, and 1.33 μM/min, respectively. In human liver microsomes (HLMs), a concentration-dependent inhibition of celecoxib hydroxylation by quinidine was observed after CYP2C9 and CYP3A4 were inhibited. In individual HLMs with variable CYP2D6 activities, a significant correlation was observed between celecoxib hydroxylation and CYP2D6-selective dextromethorphan O-demethylation when CYP2C9 and CYP3A4 activities were suppressed (r = 0...
October 2018: Drug Metabolism and Pharmacokinetics
Yaling Dou, Pan Peng, Congli Cai, Ali Ye, Lingjun Kong, Rui Zhang
HLA-B*58:01 has been demonstrated to be associated with allopurinol-induced severe cutaneous adverse reactions. Since HLA-B*58:01 is too complicated to be identified, it is necessary to select an appropriate surrogate biomarker. In Japan, the rs9263726 allele was considered as a surrogate biomarker for HLA-B*58:01, but this was not the case with the Australian cohort. Due to the conflict results, in this study, we aim to demonstrate whether the rs9263726 allele is a surrogate biomarker for HLA-B*58:01 in Han Chinese population...
October 2018: Drug Metabolism and Pharmacokinetics
Yuki Kimura, Masaki Kobayashi, Masaru Asari, Issei Higuchi, Katsuya Narumi, Ayako Furugen, Ken Iseki
MCT1 (SLC16A1), MCT4 (SLC16A3), and MCT11 (SLC16A11) are members of the monocarboxylate transporter (MCT) family. MCT1 and MCT4 transport pH-related monocarboxylates, such as lactate and pyruvate. MCT11 may also be a proton-coupled monocarboxylate transporter. Although alterations of these substrates are involved in the pathology of cancer and diabetes, little is known about MCT polymorphisms. In this study, genetic variation was evaluated in SLC16A1, SLC16A3, and SLC16A11 in the Japanese population (healthy volunteers, n = 92)...
October 2018: Drug Metabolism and Pharmacokinetics
Tomoko Kito, Sumito Ito, Tadahaya Mizuno, Kazuya Maeda, Hiroyuki Kusuhara
The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with Ki values (μM) of 0.030-0.28 and 2.4-5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with Km values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2...
September 20, 2018: Drug Metabolism and Pharmacokinetics
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