Effect of Hepatic Organic Anion‐Transporting Polypeptide 1B Inhibition and Chronic Kidney Disease on the Pharmacokinetics of a Liver‐Targeted Glucokinase Activator: A Model‐Based Evaluation

2019 ◽  
Vol 106 (4) ◽  
pp. 792-802 ◽  
Author(s):  
Arthur Bergman ◽  
Yi‐an Bi ◽  
Sumathy Mathialagan ◽  
John Litchfield ◽  
David J. Kazierad ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Organic Anion ◽  
Glucokinase Activator ◽  
Organic Anion Transporting Polypeptide ◽  
Model Based

Transcriptional Regulation of Organic Anion Transporting Polypeptide SLCO4C1 as a New Therapeutic Modality to Prevent Chronic Kidney Disease

2011 ◽  
Vol 100 (9) ◽  
pp. 3696-3707 ◽  
Author(s):  
Takehiro Suzuki ◽  
Takafumi Toyohara ◽  
Yasutoshi Akiyama ◽  
Yoichi Takeuchi ◽  
Eikan Mishima ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Transcriptional Regulation ◽  
Kidney Disease ◽  
Organic Anion ◽  
Therapeutic Modality ◽  
Organic Anion Transporting Polypeptide

scholarly journals A novel SNP in the 5’ regulatory region of organic anion transporter 1 is associated with chronic kidney disease

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Chiao-Yin Sun ◽  
Mai-Szu Wu ◽  
Chin-Chan Lee ◽  
Shu-Hong Chen ◽  
Kang-Chieh Lo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Organic Anion ◽  
Regulatory Region ◽  
Organic Anion Transporter ◽  
Anion Transporter ◽  
Novel Snp

scholarly journals Quantification of CYP3A and Drug Transporters Activity in Healthy Young, Healthy Elderly and Chronic Kidney Disease Elderly Patients by a Microdose Cocktail Approach

2021 ◽  
Vol 12 ◽  
Author(s):  
Punyabhorn Rattanacheeworn ◽  
Stephen J Kerr ◽  
Wonngarm Kittanamongkolchai ◽  
Natavudh Townamchai ◽  
Suwasin Udomkarnjananun ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Elderly Patients ◽  
Half Life ◽  
Dabigatran Etexilate ◽  
Organic Anion ◽  
Maximum Plasma ◽  
Cyp3a Activity ◽  
Cancer Resistance ◽  
Healthy Elderly

Background: Ageing and chronic kidney disease (CKD) affect pharmacokinetic (PK) parameters. Since mechanisms are related and remain unclear, cytochrome P450 (CYP) 3A and drug transporter activities were investigated in the elderly with or without CKD and compared to healthy adults using a microdose cocktail.Methods: Healthy young participants (n = 20), healthy elderly participants (n = 16) and elderly patients with CKD (n = 17) received, in study period 1, a single dose of microdose cocktail probe containing 30 µg midazolam, 750 µg dabigatran etexilate, 100 µg atorvastatin, 10 µg pitavastatin, and 50 µg rosuvastatin. After a 14-day wash-out period, healthy young participants continued to study period 2 with the microdose cocktail plus rifampicin. PK parameters including area under the plasma concentration-time curve (AUC), maximum plasma drug concentration (Cmax), and half-life were estimated before making pairwise comparisons of geometric mean ratios (GMR) between groups.Results: AUC and Cmax GMR (95% confidence interval; CI) of midazolam, a CYP3A probe substrate, were increased 2.30 (1.70–3.09) and 2.90 (2.16–3.88) fold in healthy elderly and elderly patients with CKD, respectively, together with a prolonged half-life. AUC and Cmax GMR (95%CI) of atorvastatin, another CYP3A substrate, was increased 2.14 (1.52–3.02) fold in healthy elderly and 4.15 (2.98–5.79) fold in elderly patients with CKD, indicating decreased CYP3A activity related to ageing. Associated AUC changes in the probe drug whose activity could be modified by intestinal P-glycoprotein (P-gp) activity, dabigatran etexilate, were observed in patients with CKD. However, whether the activity of pitavastatin and rosuvastatin is modified by organic anion transporting polypeptide 1B (OATP1B) and of breast cancer resistance protein (BCRP), respectively, in elderly participants with or without CKD was inconclusive.Conclusions: CYP3A activity is reduced in ageing. Intestinal P-gp function might be affected by CKD, but further confirmation appears warranted.Clinical Trial Registration:http://www.thaiclinicaltrials.org/ (TCTR 20180312002 registered on March 07, 2018)

Biomarker‐informed model‐based risk assessment of organic anion transporting polypeptide 1B mediated drug‐drug interactions

2021 ◽  
Author(s):  
Emi Kimoto ◽  
Chester Costales ◽  
Mark A. West ◽  
Yi‐an Bi ◽  
Manoli Vourvahis ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Drug Interactions ◽  
Organic Anion ◽  
Organic Anion Transporting Polypeptide ◽  
Model Based

Differentiating Suicide From Life-Ending Acts and End-of-Life Decisions: A Model Based on Chronic Kidney Disease and Dialysis

2009 ◽  
Vol 50 (1) ◽  
pp. 1-7 ◽  
Author(s):  
John Michael Bostwick ◽  
Lewis M. Cohen
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
End Of Life ◽  
End Of Life Decisions ◽  
Model Based ◽  
Life Decisions

scholarly journals Model-Based Analysis of FGF23 Regulation in Chronic Kidney Disease

2010 ◽  
Vol 4 ◽  
pp. GRSB.S4880 ◽  
Author(s):  
Hiroki Yokota ◽  
Ana Pires ◽  
João F. Raposo ◽  
Hugo G. Ferreira
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Model Based ◽  
Model Based Analysis

scholarly journals Model‐based approach for methoxy polyethylene glycol‐epoetin beta drug development in paediatric patients with anaemia of chronic kidney disease

2020 ◽  
Vol 86 (4) ◽  
pp. 801-811
Author(s):  
Pascal Chanu ◽  
Franz Schaefer ◽  
Bradley A. Warady ◽  
Claus Peter Schmitt ◽  
Bruno Reigner ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Polyethylene Glycol ◽  
Kidney Disease ◽  
Drug Development ◽  
Model Based ◽  
Epoetin Beta ◽  
Paediatric Patients ◽  
Methoxy Polyethylene Glycol

scholarly journals Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver

2014 ◽  
Vol 307 (12) ◽  
pp. R1488-R1492 ◽  
Author(s):  
Jennifer C. Ryan ◽  
Kenneth W. Dunn ◽  
Brian S. Decker
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Intravital Microscopy ◽  
Drug Transport ◽  
Cultured Cells ◽  
Organic Anion ◽  
Hepatic Clearance ◽  
Bile Canaliculi ◽  
Hepatic Transport

Clinical studies indicate that hepatic drug transport may be altered in chronic kidney disease (CKD). Uremic solutes associated with CKD have been found to alter the expression and/or activity of hepatocyte transporters in experimental animals and in cultured cells. However, given the complexity and adaptability of hepatic transport, it is not clear whether these changes translate into significant alterations in hepatic transport in vivo. To directly measure the effect of CKD on hepatocyte transport in vivo, we conducted quantitative intravital microscopy of transport of the fluorescent organic anion fluorescein in the livers of rats following 5/6th nephrectomy, an established model of CKD. Our quantitative analysis of fluorescein transport showed that the rate of hepatocyte uptake was reduced by ∼20% in 5/6th nephrectomized rats, consistent with previous observations of Oatp downregulation. However, the overall rate of transport into bile canaliculi was unaffected, suggesting compensatory changes in Mrp2-mediated secretion. Our study suggests that uremia resulting from 5/6th nephrectomy does not significantly impact the overall hepatic clearance of an Oatp substrate.

Uric acid-induced phenotypic transition of renal tubular cells as a novel mechanism of chronic kidney disease

2013 ◽  
Vol 304 (5) ◽  
pp. F471-F480 ◽  
Author(s):  
Eun-Sun Ryu ◽  
Mi Jin Kim ◽  
Hyun-Soo Shin ◽  
Yang-Hee Jang ◽  
Hack Sun Choi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Uric Acid ◽  
Kidney Disease ◽  
Organic Anion ◽  
Mesenchymal Transition ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Phenotypic Transition ◽  
E Cadherin

Recent experimental and clinical studies suggest a causal role of uric acid in the development of chronic kidney disease. Most studies have focused on uric acid-induced endothelial dysfunction, oxidative stress, and inflammation in the kidney. The direct effects of uric acid on tubular cells have not been studied in detail, and whether uric acid can mediate phenotypic transition of renal tubular cells such as epithelial-to-mesenchymal transition (EMT) is not known. We therefore investigated whether uric acid could alter E-cadherin expression and EMT in the kidney of hyperuricemic rats and in cultured renal tubular cells (NRK cells). Experimental hyperuricemia was associated with evidence of EMT before the development of significant tubulointerstitial fibrosis at 4 wk, as shown by decreased E-cadherin expression and an increased α-smooth muscle actin (α-SMA). Allopurinol significantly inhibited uric acid-induced changes in E-cadherin and α-SMA with an amelioration of renal fibrosis at 6 wk. In cultured NRK cells, uric acid induced EMT, which was blocked by the organic anion transport inhibitor probenecid. Uric acid increased expression of transcriptional factors associated with decreased synthesis of E-cadherin (Snail and Slug). Uric acid also increased the degradation of E-cadherin via ubiquitination, which is of importance since downregulation of E-cadherin is considered to be a triggering mechanism for EMT. In conclusion, uric acid induces EMT of renal tubular cells decreasing E-cadherin synthesis via an activation of Snail and Slug as well as increasing the degradation of E-cadherin.

Chronic Kidney Disease Resource

2005 ◽  
Vol 38 (9) ◽  
pp. 41
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease
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