Cooperative inhibitory effects of uremic toxins and other serum components on OATP1B1-mediated transport of SN-38

Katsube, Yurie; Tsujimoto, Masayuki; Koide, Hiroyoshi; Ochiai, Megumi; Hojyo, Ayako; Ogawa, Kokichi; Kambara, Kengo; Torii, Nao; Shima, Daisuke; Furukubo, Taku; Izumi, Shinyu; Yamakawa, Tomoyuki; Minegaki, Tetsuya; Nishiguchi, Kohshi

doi:10.1007/s00280-017-3276-y

Cited by 19 publications

(17 citation statements)

References 21 publications

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“…), indicating the presence of inhibitors of OATP1B1‐mediated pravastatin uptake in USR. We hypothesized that IS, HA, CMPF, and IAA might cooperatively inhibit OATP1B1‐mediated uptake of pravastatin because a mixture of these UTs at clinically relevant concentrations reportedly inhibited OATP1B1‐mediated SN‐38 uptake . We found that IS, CMPF, and IAA inhibited OATP1B1‐mediated uptake of pravastatin at 30 μM, but not at 300 μM, whereas HA showed an opposite effect (Figs and ).…”

Section: Discussionsupporting

confidence: 92%

Effects of Uremic Serum Residue on OATP1B1‐ and OATP1B3‐Mediated Pravastatin Uptake in OATP‐Expressing HEK293 Cells and Human Hepatocytes

et al. 2018

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Patients with end‐stage renal disease have increased plasma concentrations of statins, which is a risk factor for rhabdomyolysis, as well as elevated levels of uremic toxins (UTs). We investigated the effects of uremic serum residue and UTs on organic anion‐transporting peptide (OATP1B1)‐ and OATP1B3‐mediated pravastatin uptake. We evaluated the effects of normal serum residue with four UTs (hippuric acid, 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furan propionate, indole‐3‐acetic acid, and 3‐indoxyl sulfate) and uremic serum residue on pravastatin uptake by OATP1B1‐ or OATP1B3‐expressing HEK293 cells. Furthermore, we assessed the contribution of each transporter using cryopreserved human hepatocytes. Uremic serum residue and UTs significantly inhibited OATP1B1‐mediated pravastatin uptake. Uremic serum residue accelerated OATP1B3‐mediated pravastatin uptake, while UTs had no effect. There was no difference in pravastatin uptake between uremic‐ and normal serum residue‐treated hepatocytes. The results suggest that the effects of uremic serum on pravastatin hepatic uptake may be considered negligible in end‐stage renal disease patients.

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Section: Discussionsupporting

confidence: 92%

Effects of Uremic Serum Residue on OATP1B1‐ and OATP1B3‐Mediated Pravastatin Uptake in OATP‐Expressing HEK293 Cells and Human Hepatocytes

et al. 2018

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“…For example, irinotecan undergoes biotransformation by carboxylesterase to the active metabolite SN-38, which is a substrate of hepatic OATP1B1 and is detoxified by glucuronidation. CMPF, indoxyl sulfate, hippuric acid and indole-3-acetic acid competitively inhibit OATP-mediated transport of SN-38 in human hepatocytes and HEK 293 cells [69,85]. Decreased hepatic uptake leads to increased systemic exposure to SN-38 and toxicity.…”

Section: Effects Of Microbial Toxins Beyond Drug Metabolism and Trmentioning

confidence: 99%

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

Prokopienko

Nolin

2017

Expert Review of Clinical Pharmacology

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Introduction Scientific interest in the gut microbiota is increasing due to improved understanding of its implications in human health and disease. In patients with kidney disease, gut microbiota-derived uremic toxins directly contribute to altered nonrenal drug clearance. Microbial imbalances, known as dysbiosis, potentially increase formation of microbiota-derived toxins, and diminished renal clearance leads to toxin accumulation. High concentrations of microbiota-derived toxins such as indoxyl sulfate and p-cresol sulfate perpetrate interactions with drug metabolizing enzymes and transporters, which provides a mechanistic link between increases in drug-related adverse events and dysbiosis in kidney disease. Areas Covered This review summarizes the effects of microbiota-derived uremic toxins on hepatic phase I and phase II drug metabolizing enzymes and drug transporters. Research articles that tested individual toxins were included. Therapeutic strategies to target microbial toxins are also discussed. Expert Commentary Large interindividual variability in toxin concentrations may explain some differences in nonrenal clearance of medications. Advances in human microbiome research provide unique opportunities to systematically evaluate the impact of individual and combined microbial toxins on drug metabolism and transport, and to explore microbiota-derived uremic toxins as potential therapeutic targets.

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“…Drug plasma protein binding has also been shown to be altered in RI due to uremia, hypoalbuminemia and drug interactions with uremic toxins (Keller, Maiga, Neumayer, Lode, & Distler, ; Vanholder, Van Landschoot, De Smet, Schoots, & Ringoir, ). Uremic toxins, many of which are small organic anions such as indoxyl sulfate, can accumulate in renal impairment, and are known substrates of important DTs such as organic anion transporters (OATs), as well as other SLC transporters such as OATP1B1 and ABC transporters (Katsube et al, ; Nigam et al, ). This could result in DDI interactions in renal impairment even when no interaction is expected based on the xenobiotics administered.…”

Section: Discussionmentioning

confidence: 99%

Effects of renal impairment on transporter‐mediated renal reabsorption of drugs and renal drug–drug interactions: A simulation‐based study

Follman

Dave

Morris

2018

Biopharm & Drug Disp

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Renal impairment (RI) significantly impacts the clearance of drugs through changes in the glomerular filtration rate, protein binding and alterations in the expression of renal drug transport proteins and hepatic metabolizing enzymes. The objectives of this study were to evaluate quantitatively the effects of renal impairment on the pharmacokinetics of drugs undergoing renal transporter-mediated reabsorption. A previously published semi-mechanistic kidney model incorporating physiologically relevant fluid reabsorption and transporter-mediated active renal reabsorption (PMID: 26341876) was utilized in this study. The probe drug/transporter pair utilized was γ-hydroxybutyric acid (GHB) and monocarboxylate transporter 1 (SCL16A1, MCT1). γ-Hydroxybutyric acid concentrations in the blood and amount excreted into urine were simulated using ADAPT 5 for the i.v. dose range of 200-1500 mg/kg in rats and the impact of renal impairment on CL and AUC was evaluated. A 90% decrease in GFR resulted in a > 100-fold decrease in GHB CL . When expression of reabsorptive transporters was decreased and f was increased, CL approached GFR. The effect of renal impairment on CL was reduced when the expression of drug metabolizing enzymes (DME) was increased as a result of increased metabolic clearance; the converse held true when the DME expression was decreased. In conclusion, this study quantitatively demonstrated that the effects of renal insufficiency on the clearance of drugs is modulated by transporter expression, contribution of renal clearance to overall clearance, expression of drug metabolizing enzymes, fraction unbound and drug-drug interactions with inhibitors of renal transporters that may be increased in the presence of renal impairment.

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Cooperative inhibitory effects of uremic toxins and other serum components on OATP1B1-mediated transport of SN-38

Abstract: Hepatic uptake of SN-38 via OATP1B1 decreases in ESKD patients through cooperative inhibitory effects of UTs and serum components.

Cited by 19 publications

References 21 publications

Effects of Uremic Serum Residue on OATP1B1‐ and OATP1B3‐Mediated Pravastatin Uptake in OATP‐Expressing HEK293 Cells and Human Hepatocytes

Effects of Uremic Serum Residue on OATP1B1‐ and OATP1B3‐Mediated Pravastatin Uptake in OATP‐Expressing HEK293 Cells and Human Hepatocytes

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

Effects of renal impairment on transporter‐mediated renal reabsorption of drugs and renal drug–drug interactions: A simulation‐based study

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