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Jialin Mao, Iain Martin, James McLeod, Gail Nolan, Robert van Horn, Manoli Vourvahis, Yvonne S Lin
A key goal in the clinical development of a new molecular entity is to quickly identify whether it has the potential for drug-drug interactions. In particular, confirmation of in vitro data in the early stage of clinical development would facilitate the decision making and inform future clinical pharmacology study designs. Plasma 4β-hydroxycholesterol (4β-HC) is considered as an emerging endogenous biomarker for cytochrome P450 3A (CYP3A), one of the major drug metabolizing enzymes. Although there are increasing reports of the use of 4β-HC in academic- and industry-sponsored clinical studies, a thorough review, summary and consideration of the advantages and challenges of using 4β-HC to evaluate changes in CYP3A activity has not been attempted...
October 10, 2016: Drug Metabolism Reviews
D G Bailey
WHAT IS KNOWN AND OBJECTIVE: Grapefruit juice interacts with a number of drugs. This commentary provides feedback on a previously proposed approach for predicting clinically relevant interactions with grapefruit juice based on the average inherent oral bioavailability (F) and magnitude of increase in bioavailability with other CYP3A inhibitors of the drug. COMMENT: Additional factors such as variability of the magnitude of the pharmacokinetic interaction among individuals, product monograph cautionary statements and vulnerability of the patient population should be considered...
October 6, 2016: Journal of Clinical Pharmacy and Therapeutics
Tadatoshi Tanino, Akira Komada, Koji Ueda, Toru Bando, Yukie Nojiri, Yukari Ueda, Eiichi Sakurai
Type 1 allergic diseases are characterized by elevated production of specific immunoglobulin E (IgE) for each antigen and have become a significant health problem worldwide. This study investigated the effect of IgE-mediated allergy on drug pharmacokinetics. To further understand differential suppression of hepatic cytochrome P450 (CYP) activity, we examined the inhibitory effect of nitric oxide (NO), a marker of allergic conditions. Seven days after primary or secondary sensitization (PS7 and SS7, respectively), hepatic CYP1A2, CYP2C, CYP2E1 and CYP3A activities were decreased to 45%-75% of the corresponding control, however, CYP2D activity was not downregulated...
September 30, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
XiaoMei Zhuang, TianHong Zhang, SiJia Yue, Juan Wang, Huan Luo, YunXia Zhang, Zheng Li, JinJing Che, HaiYing Yang, Hua Li, MingShe Zhu, Chuang Lu
Icotinib (ICO), a novel small molecule and a tyrosine kinase inhibitor, was developed and approved recently in China for non-small cell lung cancer. During screening for CYP inhibition potential in human liver microsomes (HLM), heterotropic activation toward CYP3A5 was revealed. Activation by icotinib was observed with CYP3A-mediated midazolam hydroxylase activity in HLM (∼40% over the baseline) or recombinant human CYP3A5 (rhCYP3A5) (∼70% over the baseline), but not in the other major CYPs including rhCYP3A4...
September 22, 2016: Biochemical Pharmacology
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...
September 26, 2016: Biopharmaceutics & Drug Disposition
Bruce Green, Herta Crauwels, Thomas N Kakuda, Simon Vanveggel, Anne Brochot
BACKGROUND: Etravirine is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretrovirals for treatment-experienced HIV patients ≥6 years of age. Etravirine is primarily metabolized by cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A. This analysis determined the impact of concomitant antiretrovirals and CYP2C9/CYP2C19 phenotype on the pharmacokinetics of etravirine. METHODS: We used 4728 plasma concentrations from 817 adult subjects collected from four clinical studies to develop the population pharmacokinetic model...
September 24, 2016: Clinical Pharmacokinetics
M V Varma, E Kimoto, R Scialis, Y Bi, J Lin, H Eng, A S Kalgutkar, A F El-Kattan, A D Rodrigues, L M Tremaine
Montelukast, a leukotriene receptor antagonist commonly prescribed for treatment of asthma, is primarily metabolized by Cytochrome P450 (CYP)2C8, and has been suggested as a probe substrate for investigating CYP2C8 activity in vivo. We evaluated the quantitative role of hepatic uptake transport in its pharmacokinetics and drug-drug interactions (DDIs). Montelukast was characterized with significant active uptake in human hepatocytes, and showed affinity towards organic anion transporting polypeptides (OATPs) in transfected cell systems...
September 20, 2016: Clinical Pharmacology and Therapeutics
Katalin Tóth, Gábor Csukly, Dávid Sirok, Ales Belic, Ádám Kiss, Edit Háfra, Máté Déri, Ádám Menus, István Bitter, Katalin Monostory
BACKGROUND: The shortcomings of clonazepam therapy include tolerance, withdrawal symptoms, and adverse effects such as drowsiness, dizziness, and confusion leading to increased risk of falls. Inter-individual variability in the incidence of adverse events in patients partly originates from the differences in clonazepam metabolism due to genetic and nongenetic factors. METHODS: Since the prominent role in clonazepam nitro-reduction and acetylation of 7-amino-clonazepam is assigned to CYP3A and N-acetyl transferase 2 enzymes, respectively, the association between the patients' CYP3A status (CYP3A5 genotype, CYP3A4 expression) or N-acetyl transferase 2 acetylator phenotype and clonazepam metabolism (plasma concentrations of clonazepam and 7-amino-clonazepam) was evaluated in 98 psychiatric patients suffering from schizophrenia or bipolar disorders...
October 3, 2016: International Journal of Neuropsychopharmacology
Nan Shu, Mengyue Hu, Zhaoli Ling, Peihua Liu, Fan Wang, Ping Xu, Zeyu Zhong, Binbin Sun, Mian Zhang, Feng Li, Qiushi Xie, Xiaodong Liu, Li Liu
Liver injury is a common adverse effect of atorvastatin. This study aimed to investigate atorvastatin-induced hepatotoxicity in diabetic rats induced by high-fat diet combined with streptozotocin. The results showed that 40 mg/kg atorvastatin was lethal to diabetic rats, whose mean survival time was 6.2 days. Severe liver injury also occurred in diabetic rats treated with 10 mg/kg and 20 mg/kg atorvastatin. The in vitro results indicated that atorvastatin cytotoxicity in hepatocytes of diabetic rats was more severe than normal and high-fat diet feeding rats...
2016: Scientific Reports
Ayman F El-Kattan, Manthena V Varma, Stefan J Steyn, Dennis O Scott, Tristan S Maurer, Arthur Bergman
PURPOSE: To assess the utility of Extended Clearance Classification System (ECCS) in understanding absorption, distribution, metabolism, and elimination (ADME) attributes and enabling victim drug-drug interaction (DDI) predictions. METHODS: A database of 368 drugs with relevant ADME parameters, main metabolizing enzymes, uptake transporters, efflux transporters, and highest change in exposure (%AUC) in presence of inhibitors was developed using published literature...
September 12, 2016: Pharmaceutical Research
Rangaraj Narayanan, Matthew Hoffmann, Gondi Kumar
BACKGROUND: Oncology therapy typically involves drug combinations since monotherapy seldom provides the desired outcome. But combination therapy presents the potential for drug-drug interactions (DDIs). Due to the narrow window between therapeutic concentrations and onset of toxicity often observed with oncology therapeutics, managing DDIs with combination therapy in cancer is critical. Physiologically based pharmacokinetic (PBPK) modeling can be effectively used for predicting DDIs and guiding dose-selection, but requires development of PBPK models of cancer drugs...
July 29, 2016: Drug Metabolism Letters
Hiromi Soraoka, Kentaro Oniki, Kazuki Matsuda, Tatsumasa Ono, Kosuke Taharazako, Yoshihiro Uchiyashiki, Ryoko Kamihashi, Ayana Kita, Ayaka Takashima, Kazuko Nakagawa, Norio Yasui-Furukori, Daisuke Kadowaki, Keishi Miyata, Junji Saruwatari
The concomitant use of herb and prescription medications is increasing globally. Herb-drug interactions are therefore a clinically important problem. Yokukansan (YKS), a Japanese traditional herbal medicine, is one of the most frequently used herbal medicines. It is effective for treating the behavioral and psychological symptoms of dementia. We investigated the potential effects of YKS on drug-metabolizing enzyme activities in humans. An open-label repeat-dose study was conducted in 26 healthy Japanese male volunteers (age: 22...
2016: Biological & Pharmaceutical Bulletin
Hikaru Sato, Takafumi Naito, Takuya Ishida, Junichi Kawakami
PURPOSE: Elevated serum proinflammatory cytokines are associated with the reduction of cytochrome P450 enzyme (CYP) activity. This study aimed to evaluate the oxycodone pharmacokinetics, central symptoms, and serum proinflammatory cytokines based on cachexia stage in cancer patients. METHODS: Forty-seven cancer patients receiving extended-release oxycodone were enrolled. Predose plasma concentrations of oxycodone and its metabolites were normalized with the daily dose and body weight...
August 26, 2016: European Journal of Clinical Pharmacology
Mahmoud Hasan, Werner Siegmund, Stefan Oswald
Cytochrome P450 3A (CYP) enzymes are involved in the elimination of many drugs and are known to be regulated by several environmental factors. Thus, it was the aim of this study to develop and validate an analytical method allowing estimation of the hepatic CYP3A enzyme activity using the 4-hydroxycholesterol to cholesterol ratio as an endogenous biomarker in serum. Both compounds were isolated from the biological matrix by liquid-liquid extraction using n-hexane after saponification with ethanolic sodium methoxide solution (2M) to cleave the steroids from their esterified forms without any kind of further derivatization...
October 15, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Hanna Nylén, Abiy Habtewold, Eyasu Makonnen, Getnet Yimer, Leif Bertilsson, Jürgen Burhenne, Ulf Diczfalusy, Eleni Aklillu
Initiation of efavirenz-based combination antiretroviral therapy (cART) is associated with Vitamin D deficiency, but the risk factors including efavirenz pharmacokinetics for cART-induced severe vitamin D deficiency (SVDD) and the impact of anti-tuberculosis (TB) cotreatment are not explored. We investigated the prevalence of SVDD in HIV and TB-HIV coinfected patients and associated risk factors for treatment-induced SVDD.Treatment-naïve Ethiopian HIV patients with (n = 102) or without (n = 89) TB co-infection were enrolled prospectively and received efavirenz-based cART...
August 2016: Medicine (Baltimore)
Ahmed Hamed Salem, Suresh K Agarwal, Martin Dunbar, Sari L Heitner Enschede, Rod A Humerickhouse, Shekman L Wong
Venetoclax is a selective BCL-2 inhibitor that is now approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors as well as low and high fat meals on venetoclax pharmacokinetics...
August 25, 2016: Journal of Clinical Pharmacology
Devin M Swanson, Brad M Savall, Kevin J Coe, Freddy Schoetens, Tatiana Koudriakova, Judith Skaptason, Jessica Wall, Jason Rech, Xiahou Deng, Meri De Angelis, Anita Everson, Brian Lord, Qi Wang, Hong Ao, Brian Scott, Kia Sepassi, Timothy W Lovenberg, Nicholas I Carruthers, Anindya Bhattacharya, Michael A Letavic
The synthesis and SAR of a series of 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine P2X7 antagonists are described. Addressing P2X7 affinity and liver microsomal stability issues encountered with this template afforded methyl substituted 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridines ultimately leading to the identification of 1 (JNJ 54166060). 1 is a potent P2X7 antagonist with an ED50 = 2.3 mg/kg in rats, high oral bioavailability and low-moderate clearance in preclinical species, acceptable safety margins in rats, and a predicted human dose of 120 mg of QD...
September 22, 2016: Journal of Medicinal Chemistry
Zhenzhen Sun, Zhan Zhang, Minghui Ji, Hongbao Yang, Meghan Cromie, Jun Gu, Chao Wang, Lu Yang, Yongquan Yu, Weimin Gao, Shou-Lin Wang
Cytochrome P450 3A (CYP3A) is the most abundant CYP450 enzyme in the liver and is involved in the metabolism of over 50% of xenobiotics. Our previous studies revealed that 2,2',4,4'-tetrabromodiphenyl ether (BDE47) could induce rat CYP3A1 expression, but the molecular basis remains unclear. Using in silico analysis, we identified a potential miR-23b recognition element (MRE23b) in the 3'-UTR region of CYP3A1 mRNA, which was verified by the luciferase assay. The miR-23b mimic and inhibitor significantly down- and up-regulated the expression of CYP3A1, respectively...
2016: Scientific Reports
Peter N Morcos, Yumi Cleary, Elena Guerini, Georgina Dall, Katrijn Bogman, Luigi De Petris, Santiago Viteri, Walter Bordogna, Li Yu, Meret Martin-Facklam, Alex Phipps
The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small-cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from three fixed-sequence studies evaluating drug-drug interactions for alectinib through CYP3A...
August 22, 2016: Clinical Pharmacology in Drug Development
Yunting Zhu, Liang Li, Ge Zhang, Hong Wan, Changyong Yang, Xingxing Diao, Xiaoyan Chen, Lianshan Zhang, Dafang Zhong
Pyrotinib is a novel irreversible tyrosine kinase inhibitor developed for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The results of phase I clinical trial demonstrated that pyrotinib was well tolerated and exhibited potent antitumor activity. As a promising therapeutic agent for HER2-positive breast cancer, it is of great importance to investigate the biotransformation of pyrotinib in humans and identify the major enzymes involved in its metabolism during its early stage of development for safety consideration...
October 15, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
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