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Renal excretion of drugs

Benjamin Wu, Murad Melhem, Raju Subramanian, Ping Chen, Bethlyn Jaramilla Sloey, Bruno Fouqueray, M Benjamin Hock, Gary L Skiles, Andrew T Chow, Edward Lee
Etelcalcetide, a d-amino acid peptide, is an intravenous calcimimetic approved for the treatment of secondary hyperparathyroidism. Etelcalcetide binds the calcium-sensing receptor and increases its sensitivity to extracellular calcium, thereby decreasing secretion of parathyroid hormone (PTH) by chief cells. Etelcalcetide and its low-molecular-weight transformation products are rapidly cleared by renal excretion in healthy subjects, but clearance is substantially reduced and dependent on hemodialysis in end-stage renal disease...
March 13, 2018: Journal of Clinical Pharmacology
Milton Packer
Three classes of anti-hyperglycaemic medications are distinguished by their urinary sodium excretion-enhancing and blood pressure-lowering actions: long-acting glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors. Yet, these drugs exert different effects on macrovascular risk. Glucagon-like peptide-1 receptor agonists reduce atherosclerotic thromboembolic events, but have little effect on heart failure; sodium-glucose co-transporter-2 inhibitors decrease the occurrence of heart failure, but have minimal effect on myocardial infarction and stroke; and dipeptidyl peptidase-4 inhibitors do not ameliorate either atherosclerotic thromboembolic events or heart failure...
March 12, 2018: Diabetic Medicine: a Journal of the British Diabetic Association
Milton Packer
Although dipeptidyl peptidase (DPP)-4 inhibitors have been reported to have a neutral effect on thromboembolic vaso-occlusive events in large-scale trials, they act to potentiate several endogenous peptides that can exert deleterious cardiovascular effects. Experimentally, DPP-4 inhibitors may augment the ability of glucagon-like peptide-1 to stimulate cyclic adenosine monophosphate in cardiomyocytes, and potentiation of the effects of stromal cell-derived factor-1 by DPP-4 inhibitors may aggravate cardiac fibrosis...
March 1, 2018: JACC. Heart Failure
Hiroko Hashimoto, Naohiro Nomura, Wakana Shoda, Kiyoshi Isobe, Hiroaki Kikuchi, Kouhei Yamamoto, Takuya Fujimaru, Fumiaki Ando, Takayasu Mori, Tomokazu Okado, Tatemitsu Rai, Shinichi Uchida, Eisei Sohara
OBJECTIVE: Metformin is an antidiabetic drug that is widely used to treat patients with diabetes mellitus. Recent studies have reported that treatment with metformin not only improved blood glucose levels but also reduced blood pressure. However, it remains unclear how metformin reduces blood pressure. We hypothesized that metformin affects sodium reabsorption in the kidneys. METHODS: Urinary sodium excretion and expression of renal sodium transporters were examined in 8-week-old male C57BL/6 mice with acute and chronic treatment of metformin...
March 3, 2018: Metabolism: Clinical and Experimental
Abdul Aziz Al Wazzan, Eline Tommelein, Katrien Foubert, Stefano Bonassi, Graziano Onder, Annemie Somers, Mirko Petrovic, Koen Boussery
BACKGROUND: Renal function progressively worsens with age. Potentially inappropriate prescribing (PIP) of renally excreted active drugs (READs) is common in older adults, leading to an increased rate of iatrogenic illness. The Ghent Older People's Prescription community Pharmacy Screening (GheOP3 S-) tool is an effective, explicit instrument that was developed for community pharmacists (CPs) to detect PIP. So far, this tool does not assess PIP of the frequently used READs in older patients with renal impairment...
March 5, 2018: Drugs & Aging
Keizo Kanasaki
Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors used to treat type 2 diabetes may have nephroprotective effects beyond the reduced renal risk conferred by glycemic control. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. The kidneys contain the highest levels of DPP-4, which is increased in diabetic nephropathy. DPP-4 inhibitors are a chemically heterogeneous class of drugs with important pharmacological differences. Of the globally marketed DPP-4 inhibitors, linagliptin is of particular interest for diabetic nephropathy as it is the only compound that is not predominantly excreted in the urine...
February 28, 2018: Clinical Science (1979-)
Ke Wang, Bryan Kestenbaum
The secretion of small molecules by the proximal tubules of the kidneys represents a vital homeostatic function for rapidly clearing endogenous solutes and medications from the circulation. After filtration at the glomerulus, renal blood flow is directed through a network of peritubular capillaries, where transporters of the proximal tubules actively secrete putative uremic toxins and hundreds of commonly prescribed drugs into the urine, including protein-bound substances that cannot readily cross the glomerular basement membrane...
February 28, 2018: Clinical Journal of the American Society of Nephrology: CJASN
Sergey Aksenov, Carl C Peck, Ulf G Eriksson, Donald R Stanski
To provide insight into pharmacological treatment of hyperuricemia we developed a semi-mechanistic, dynamical model of uric acid (UA) disposition in human. Our model represents the hyperuricemic state in terms of production of UA (rate, PUA), its renal filtration (glomerular filtration rate, GFR) and proximal tubular reabsorption (fractional excretion coefficient, FE). Model parameters were estimated using data from 9 Phase I studies of xanthine oxidase inhibitors (XOI) allopurinol and febuxostat and a novel uricosuric, the selective UA reabsorption inhibitor lesinurad, approved for use in combination with a XOI...
March 2018: Physiological Reports
Shun Huang, Yanjiang Han, Min Chen, Kongzhen Hu, Yongshuai Qi, Penghui Sun, Men Wang, Hubing Wu, Guiping Li, Quanshi Wang, Zhiyun Du, Kun Zhang, Suqing Zhao, Xi Zheng
Epidermal growth factor receptor (EGFR) has gained significant attention as a therapeutic target. Several EGFR targeting drugs (Gefitinib and Erlotinib) have been approved by US Food and Drug Administration (FDA) and have received high approval in clinical treatment. Nevertheless, the curative effect of these medicines varied in many solid tumors because of the different levels of expression and mutations of EGFR. Therefore, several PET radiotracers have been developed for the selective treatment of responsive patients who undergo PET/CT imaging for tyrosine kinase inhibitor (TKI) therapy...
September 1, 2017: Bioorganic & Medicinal Chemistry Letters
Lovic Dragan, Manolis Kallistratos, Constantinos Tsioufis, Charalampos Grassos, Dragan Djordjevic, Ivan Tasic, Athanasios Manolis, Andreas Pittaras
BACKGROUND: The impact of overt diabetes and poor glycemic control on the risk of cardiovascular disease is well established. Among patients with type 2 diabetes, several studies demonstrated a significant increase in coronary artery disease related death and cardiovacular events associated with HbA1c levels of greater than 7 % compared with lower levels. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a novel class of anti-diabetic drugs that lower blood glucose levels through the suppression of renal glucose reabsorption thereby promoting renal glucose excretion...
February 26, 2018: Cardiovascular & Hematological Disorders Drug Targets
Mahakpreet Singh, Anoop Kumar
Sodium glucose co-transport 2 inhibitors (SGLT2-i) are the new class of anti-diabetic medications which are the recently approved (2013) by FDA for the treatment of diabetes. These inhibitors block the SGLT2 protein which involved in glucose reabsorption from proximal renal tubule which results in increased glucose excretion and lower blood glucose levels. These inhibitors exert favourable effects beyond glucose control such as consistent body weight, blood pressure, and serum uric acid reductions. Canagliflozin, Dapagliflozin, and Empagliflozin belong to the class of SGLT2 inhibitors...
February 25, 2018: Current Drug Safety
Sisi Cao, Xiao-Li Dong, Ming-Xian Ho, Wen-Xuan Yu, Ka-Chun Wong, Xin-Sheng Yao, Man-Sau Wong
Oleanolic acid (OA) is a triterpenoid with reported bone anti-resorption activities. The present study aimed to characterize its bone protective effects in vivo and to study its effects on vitamin D metabolism, both in vivo and in vitro. OA significantly increased bone mineral density, improved micro-architectural properties, reduced urinary Ca excretion, increased 1,25(OH)₂D₃ and renal CYP27B1 mRNA expression in mature C57BL/6 ovariectomised (OVX) mice. OA also improved bone properties, Ca balance, and exerted modulatory effects on renal CYP27B1 and CYP24A1 expressions in aged normal female Sprague-Dawley rats...
February 22, 2018: Nutrients
Chunying Gao, Michael Z Liao, Lyrialle W Han, Kenneth E Thummel, Qingcheng Mao
Vitamin D3 is an important prohormone critical for maintaining calcium and phosphate homeostasis in the body and regulating drug-metabolizing enzymes and transporters. 25OHD3 , the most abundant circulating metabolite of vitamin D3 , is further transformed to the biologically active metabolite 1α,25-(OH)2 D3 by CYP27B1 in the kidney and extra-renal tissues, and to non-active metabolites by other CYP enzymes. In addition, 25OHD3 undergoes sulfonation and glucuronidation in the liver, forming two major conjugative metabolites, 25OHD3 -3- O -sulfate (25OHD3 -S) and 25OHD3 -3- O -glucuronide (25OHD3 -G), both of which were detected in human blood and bile...
February 21, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Yan-Rong Ma, Xuan Luo, Yan-Fang Wu, Tiffany Zhang, Fan Zhang, Guo-Qiang Zhang, Xin-An Wu
The kidney plays a major part in the elimination of many drugs and their metabolites, and drug-induced kidney injury commonly alters either glomerular filtration or tubular transport, or both. However, the renal excretion pathway of drugs has not been fully elucidated at different stages of renal injury. This study aimed to evaluate the alteration of renal excretion pathways in gentamicin (GEN)-induced renal injury in rats. Results showed that serum cystatin C, creatinine and urea nitrogen levels were greatly increased by the exposure of GEN (100 mg kg-1 ), and creatinine concentration was increased by 39...
February 20, 2018: Journal of Applied Toxicology: JAT
Ruijuan Xu, Weihong Ge, Qing Jiang
PURPOSE: Rivaroxaban is a direct oral anticoagulant with a large inter-individual variability. The present study is to develop a physiologically based pharmacokinetic (PBPK) model to predict several scenarios in clinical practice. METHODS: A whole-body PBPK model for rivaroxaban, which is metabolized by the cytochrome P450 (CYP) 3A4/5, 2J2 pathways and excreted via kidneys, was developed to predict the pharmacokinetics at different doses in healthy subjects and patients with hepatic or renal dysfunction...
February 17, 2018: European Journal of Clinical Pharmacology
Emiko Sato, An Yi Wang, Michihiro Satoh, Yoko Nishikiori, Ikuko Oba-Yabana, Mai Yoshida, Hiroshi Sato, Sadayoshi Ito, Wataru Hida, Takefumi Mori
Background: Inflammation, intrarenal renin-angiotensin system activation, oxidative stress, and carbonyl stress have been postulated to play a fundamental role in controlling blood pressure. However, little is known about the association among renal renin-angiotensin system activation, carbonyl stress, and blood pressure elevation. Methods: We evaluated the relationship between blood pressure elevation and either renal renin-angiotensin system activity or carbonyl stress in the general population (N=355) in Japan...
February 8, 2018: American Journal of Hypertension
A T Layton, V Vallon
No abstract text is available yet for this article.
February 8, 2018: Acta Physiologica
Ryoko Harada, Kenji Ishikura, Shunsuke Shinozuka, Naoaki Mikami, Riku Hamada, Hiroshi Hataya, Yoshihiko Morikawa, Tae Omori, Hirotaka Takahashi, Yuko Hamasaki, Tetsuji Kaneko, Kazumoto Iijima, Masataka Honda
BACKGROUND: In pediatric patients, due to variations in baseline serum creatinine (Cr) reference values, renal dysfunctions sometimes go unnoticed. In addition, renally excreted drugs need dose adjustment while nephrotoxic drugs should be avoided altogether in patients with impaired renal function. However, most physicians are apparently unaware of these facts and may administer these drugs to vulnerable patients. METHODS: We administered a questionnaire to all physicians and pharmacists specializing in pediatric medical care at six Tokyo metropolitan government-run hospitals in Japan...
February 6, 2018: Clinical and Experimental Nephrology
Paula Cox-North, Kelsey L Hawkins, Sean T Rossiter, Marie N Hawley, Renuka Bhattacharya, Charles S Landis
Sofosbuvir (SOF) is a nonstructural 5B polymerase inhibitor with activity in all hepatitis C virus (HCV) genotypes and is the backbone of many anti-HCV drug regimens. SOF is converted into inactive metabolites that undergo renal excretion. Patients with an estimated glomerular filtration rate (eGFR) < 30 mL/minute/1.73 m 2 may experience increased drug exposure and thus potential toxicities along with decreased efficacy due to dose reduction or drug discontinuation. This is a single-center study evaluating safety and effectiveness of SOF-based regimens in patients with severe renal dysfunction, defined as eGFR <30 mL/minute/1...
May 2017: Hepatology Communications
Kumiko Shiba, Kyoichiro Tsuchiya, Chikara Komiya, Yasutaka Miyachi, Kentaro Mori, Noriko Shimazu, Shinobu Yamaguchi, Naomi Ogasawara, Makoto Katoh, Michiko Itoh, Takayoshi Suganami, Yoshihiro Ogawa
Sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic drug, promotes urinary excretion of glucose by blocking its reabsorption in the renal proximal tubules. It is unclear whether SGLT2 inhibition could attenuate nonalcoholic steatohepatitis (NASH) and NASH-associated hepatocellular carcinoma. We examined the preventive effects of an SGLT2 inhibitor canagliflozin (CANA) in Western diet (WD)-fed melanocortin 4 receptor-deficient (MC4R-KO) mice, a mouse model of human NASH. An eight-week CANA treatment attenuated hepatic steatosis in WD-fed MC4R-KO mice, with increased epididymal fat mass without inflammatory changes...
February 5, 2018: Scientific Reports
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