Liver uptake of cefditoren is mediated by OATP1B1 and OATP2B1 in humans and Oatp1a1, Oatp1a4, and Oatp1b2 in rats

Wang, Hepeng; Sun, Pengyuan; Wang, Changyuan; Meng, Qiang; Liu, Zhihao; Huo, Xiaokui; Sun, Huijun; Ma, Xiaodong; Peng, Jinyong; Liu, Kexin

doi:10.1039/c7ra03537c

Cited by 5 publications

(4 citation statements)

References 53 publications

(73 reference statements)

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“…Since a direct use of compound 19 for in vivo proof-of-concept studies was precluded due to its poor pharmacokinetic profile, we then envisioned a study design that would still allow the evaluation of this compound in vivo. Since the exposure of compound 19 was restricted by interactions with transporters in the small intestine, but especially in the liver, we hypothesized that its coadministration with the known OATP/MRP2 inhibitor rifampicin would have a beneficial effect on plasma exposure of compound 19 . − Indeed, the mean exposure of compound 19 could be increased by a factor of 6 after iv administration and a factor of 85 after po administration, when dosed to rats which had been pretreated with rifampicin. This observation clearly supports our hypothesis that the above-mentioned transporters are responsible for restricted absorption and high hepatic clearance of compound 19 .…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Pharmacological Evaluation of Potent Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor (GLP-1R)

et al. 2019

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The therapeutic success of peptidic GLP-1 receptor agonists for treatment of type 2 diabetes mellitus (T2DM) motivated our search for orally bioavailable small molecules that can activate the GLP-1 receptor (GLP-1R) as a well-validated target for T2DM. Here, the discovery and characterization of a potent and selective positive allosteric modulator (PAM) for GLP-1R based on a 3,4,5,6-tetrahydro-1H-1,5-epiminoazocino[4,5-b]indole scaffold is reported. Optimization of this series from HTS was supported by a GLP-1R ligand binding model. Biological in vitro testing revealed favorable ADME and pharmacological profiles for the best compound 19. Characterization by in vivo pharmacokinetic and pharmacological studies demonstrated that 19 activates GLP-1R as positive allosteric modulator (PAM) in the presence of the much less active endogenous degradation product GLP1(9–36)NH2 of the potent endogenous ligand GLP-1(7–36)NH2. While these data suggest the potential of small molecule GLP-1R PAMs for T2DM treatment, further optimization is still required towards a clinical candidate.

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Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Pharmacological Evaluation of Potent Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor (GLP-1R)

et al. 2019

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“…Previous study had confirmed that cefditoren was the substrate of H+/peptide symporters PEPT1 . And the hepatic uptake of cefditoren was mediated by Oatp1a1, Oatp1a4 and Oatp1b2 and Mrp2 mediated the biliary excretion in rat . As for cefdinir, it was a poor substrate of PEPT1 and PEPT2, it was only confirmed as the substrate of OAT1 and OAT3 in kidney .…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that cefditoren was the substrate of H+/peptide symporters PEPT1 . And the hepatic uptake and biliary excretion of cefditoren were mediated by organic anion‐transporting polypeptide 1B1 (OATP1B1) and OATP2B1 in human, and Oatp1a1, Oatp1a4, Oatp1b2 and multidrug resistance‐associated protein 2 (Mrp2) in rats . As for cefdinir, it was a poor substrate of PEPT1 and PEPT2, it just only reported that cefdinir was a substrate of organic anion transporter 1 (OAT1) and OAT3 in kidney .…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic changes of cefdinir and cefditoren and its molecular mechanisms in acute kidney injury in rats

Wang

Sun

Wang

et al. 2018

Journal of Pharmacy and Pharmacology

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The molecular mechanism of decreased expression of Oat1 and Oat3 was achieved through activating p53, and then increasing the expression of Bax and Caspase-3 and down regulating Bcl-2 in AKI rats. On this basis, the cumulative urinary excretion of cefdinir was significantly decreased and the plasma concentration of cefdinir was remarkably increased in AKI rats. However, the pharmacokinetic changes of cefditoren were not observed. Accordingly, cephalosporin antibiotics such as cefditoren should be firstly selected for the treatment in patients with AKI in clinic.

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“…In order to conform the similar role of transporters in mice, uptake studies using mice tissue slices were carried out as described previously 17 . Briefly, Kunming mice were anesthetized with urethane and their kidneys and livers were incised, decapsulated, and placed in ice-cold oxygenated incubation buffer (120 mmol/L NaCl, 16.2 mmol/L KCl, mmol/L CaCl 2 , 1.2 mmol/L MgSO 4 , and 10 mmol/L Na 2 HPO 4 , pH 7.5).…”

Section: Methodsmentioning

confidence: 99%

Transporters (OATs and OATPs) contribute to illustrate the mechanism of medicinal compatibility of ingredients with different properties in yuanhuzhitong prescription

Wang

Hong

et al. 2020

Acta Pharmaceutica Sinica B

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Various medicinal ingredients with different tastes are combined according to the theory of compatibility in Chinese materia medica to achieve a better efficacy, while the mechanism was not very clear. Here, the authors studied the interaction between ingredients and human transporters such as the kidney transporters OAT1 and OAT3, the liver transporters OATP1B1 and OATP1B3, and the intestine transporter OATP2B1 to discern the compatibility mechanism of ingredients with different tastes in the Yuanhuzhitong preparation (YHP) comprising Corydalis yanhusuo (CYH) and Angelica dahurica (AD), which could relieve pain by restraining the central system. The results show that tetrahydropalmatine (TDE), the major component of CYH, could be transported by OAT3 into kidney, OATP1B1 and OATP1B3 into liver, while imperatorin (IPT) and isoimperatorin (ISP), the two key components of AD, and AD extract showed strong inhibition to OAT1 and OAT3. What's more, AD extract also exerted strongly inhibition to human transporters OATP1B1 and OATP1B3. It was also detected that IPT, ISP, and AD extract significantly downregulated the expression of Oatp1a1 , Oatp1a4 , and Oatp1b2 of liver in mice. The in vivo results show that the concentration of TDE in liver and kidney significantly decreased, while the TDE concentration in blood and brain were both significantly enhanced in the presence of IPT, ISP, and AD extract. These results suggest that the ingredients in AD with pungent taste could enhance the exposure of TDE in blood and brain by inhibiting the uptake of TDE in liver and kidney. That is to say, TDE with bitter taste could “flood up” into the central nervous system to play its therapeutic effect by the cut-off of that into liver and kidney in the presence of ingredients within AD. This paper not only proves the meridian distribution of CYH in liver and kidney with the role of OAT3, OATP1B1, and OATP1B3, but also illustrates how to improve the efficacy of CYH by reasonable compatibility with AD. This study may offer a valuable clue to illustrate the mechanism of compatibility theory.

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Liver uptake of cefditoren is mediated by OATP1B1 and OATP2B1 in humans and Oatp1a1, Oatp1a4, and Oatp1b2 in rats

Abstract: OATPs and Oatps mediated liver uptake of cefditoren in humans and in rats.

Cited by 5 publications

References 53 publications

Design, Synthesis, and Pharmacological Evaluation of Potent Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor (GLP-1R)

Design, Synthesis, and Pharmacological Evaluation of Potent Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor (GLP-1R)

Pharmacokinetic changes of cefdinir and cefditoren and its molecular mechanisms in acute kidney injury in rats

Transporters (OATs and OATPs) contribute to illustrate the mechanism of medicinal compatibility of ingredients with different properties in yuanhuzhitong prescription

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