Solvent-based formulations for intravenous mouse pharmacokinetic studies: tolerability and recommended solvent dose limits

Thackaberry, Evan A.; Wang, Xiaojing; Schweiger, Michelle; Messick, Kirsten; Valle, Nicole; Dean, Brian; Sambrone, Amy; Bowman, Terri; Xie, Minli

doi:10.3109/00498254.2013.845706

Cited by 38 publications

(24 citation statements)

References 11 publications

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“…Given the in vitro effects of NMP described above, combined with its favorable safety profile, we tested its in vivo efficacy. We first confirmed previous safety assessments of NMP 34,47 . Adult C57BL6/J mice (8-12 weeks old) were injected i.v.…”

Section: Nmp Activates Klf2 Transcriptionsupporting

confidence: 84%

The pharmaceutical solvent N-methyl-2-pyrollidone (NMP) attenuates inflammation through Krüppel-like factor 2 activation to reduce atherogenesis

Roche-Molina

Hardwick

Sánchez‐Ramos

et al. 2020

Sci Rep

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N-methyl-2-pyrrolidone (NMP) is a versatile water-miscible polar aprotic solvent. It is used as a drug solubilizer and penetration enhancer in human and animal, yet its bioactivity properties remain elusive. Here, we report that NMP is a bioactive anti-inflammatory compound well tolerated in vivo, that shows efficacy in reducing disease in a mouse model of atherosclerosis. Mechanistically, NMP increases the expression of the transcription factor Kruppel-like factor 2 (KLF2). Monocytes and endothelial cells treated with NMP express increased levels of KLF2, produce less pro-inflammatory cytokines and adhesion molecules. We found that NMP attenuates monocyte adhesion to endothelial cells inflamed with tumor necrosis factor alpha (TNF-α) by reducing expression of adhesion molecules. We further show using KLF2 shRNA that the inhibitory effect of NMP on endothelial inflammation and subsequent monocyte adhesion is KLF2 dependent. Enhancing KLF2 expression and activity improves endothelial function, controls multiple genes critical for inflammation, and prevents atherosclerosis. Our findings demonstrate a consistent effect of NMP upon KLF2 activation and inflammation, biological processes central to atherogenesis. Our data suggest that inclusion of bioactive solvent NMP in pharmaceutical compositions to treat inflammatory disorders might be beneficial and safe, in particular to treat diseases of the vascular system, such as atherosclerosis. Atherosclerosis poses a significant burden to healthcare systems throughout the world. Without access to new, inexpensive treatments, atherosclerosis and its associated cardiovascular complications will likely remain a leading cause of morbidity and mortality worldwide 1. A compelling body of evidence now describes the importance of endothelial dysfunction and inflammation during the development of atherosclerosis 2 , evidence which has driven the pharmaceutical industry to target inflammatory pathways in the quest for novel therapeutic strategies 3-5. The classical view states that the initial step of inflammation during atherosclerosis depends on the activation of the vascular endothelium 6. It is now evident that biomechanical forces exerted upon the endothelial layers by blood flow play a significant role in the resolution of inflammatory insults 7,8. Gene expression studies have demonstrated major differences in the transcriptional profile exerted upon the endothelium by a healthy, laminar blood flow compared to the complex and turbulent flow associated with early sites of atherosclerotic lesions 6,9,10. These studies have been extensively recapitulated in in vitro studies on endothelial cell monolayers

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Section: Nmp Activates Klf2 Transcriptionsupporting

confidence: 84%

The pharmaceutical solvent N-methyl-2-pyrollidone (NMP) attenuates inflammation through Krüppel-like factor 2 activation to reduce atherogenesis

Roche-Molina

Hardwick

Sánchez‐Ramos

et al. 2020

Sci Rep

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“…A preliminary safety study was performed, and the body weight, food consumption and hematological parameters of mice did not change after implantation of the pump with 1‐aminobenzotriazole at 20 and 60 mg/pump for 16 days (, ), suggesting that 1‐aminobenzotriazole is well tolerated in mice with no overt toxicity. In addition, the doses of N , N ‐dimethylacetamide and Tween 80 used in this study were lower than the nontoxic doses and no cell toxicity in tissues was caused by the vehicle on microscopical findings (data not shown).…”

Section: Resultsmentioning

confidence: 84%

In vivo use of the CYP inhibitor 1‐aminobenzotriazole to increase long‐term exposure in mice

Watanabe

Mayumi

Nishimura

et al. 2016

Biopharm & Drug Disp

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1-Aminobenzotriazole (ABT) is a well-known in vivo nonspecific inhibitor of cytochrome P450 (CYP) enzymes. An effective dosing regimen of ABT for a multiple-administration study is needed to conduct pharmacological studies for proof-of-concept, although it has been established for single-administration study, to characterize the pharmacokinetics of drug candidates. This study demonstrated a suitable dosing vehicle of ABT for continuous administration and increased exposure to antipyrine, which is a nonspecific probe of CYP, using ABT for a long period in mice. The dosing vehicle of ABT was 0.5% (w/v) hydroxypropyl methylcellulose and 0.5% (v/v) Tween 80 in N,N-dimethylacetamide/20% hydroxypropyl-β-cyclodextrin aqueous solution (2:8, v/v) based on the duration of apparent solubility. After implantation of an ALZET osmotic pump with ABT, the plasma concentrations of ABT were maintained at more than 4.1 μg/ml over 336 h. Compared with the vehicle group, the CLtot of antipyrine with ABT decreased to approximately one-fourth, and the BA of antipyrine with ABT increased up to 3-fold. In addition, the enhancement of exposure of antipyrine by ABT was maintained over the 336 h. The body weight, food consumption and hematological parameters of mice did not change with ABT administration for 16 days. These findings demonstrated that pretreatment of ABT can increase long-term exposure using continuous administration with the ALZET osmotic pump in mice with no overt toxicity. It is concluded that the in vivo use of 1-aminobenzotriazole can be applied to pharmacological studies for proof-of-concept, thus contributing to the selection of drug candidates at an early drug discovery stage. Copyright © 2016 John Wiley & Sons, Ltd.

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“…We gave 12.5 mg/kg of Nec1s in two doses 15 minutes before and 15 minutes after IRI. The Nec1s was dissolved in 30% DMSO (shown to be nontoxic by Thackaberry et al), diluted in warm saline, and injected intravenously. Control mice received an equal volume of DMSO in saline.…”

Section: Methodsmentioning

confidence: 99%

Influence of Fat on Differential Receptor Interacting Serine/Threonine Protein Kinase 1 Activity Leading to Apoptotic Cell Death in Murine Liver Ischemia Reperfusion Injury Through Caspase 8

Kolachala¹,

Palle²,

Shen³

et al. 2019

Hepatol Commun

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Current understanding is that receptor interacting serine/threonine protein kinase 1 (RIPK1) can lead to two distinct forms of cell death: RIPK3‐mediated necroptosis or caspase 8 (Casp8)‐mediated apoptosis. Here, we report that RIPK1 signaling is indispensable for protection from hepatocellular injury in a steatotic liver undergoing ischemia reperfusion injury (IRI) but not in the lean liver. In lean liver IRI, RIPK1‐mediated cell death is operational, leading to protection in RIP1 kinase‐dead knock‐in (RIPK1 K45A ) mice and necrostatin‐1s (Nec1s)‐treated lean wild‐type (WT) mice. However, when fed a high‐fat diet (HFD), RIPK1 K45A ‐treated and Nec1s‐treated WT mice undergoing IRI demonstrate exacerbated hepatocellular injury along with decreased RIPK1 ubiquitylation. Furthermore, we demonstrate that HFD‐fed RIPK3 –/– /Casp8 –/– mice show protection from IRI, but HFD‐fed RIPK3 –/– /Casp8 –/+ mice do not. We also show that blockade of RIPK1 leads to increased Casp8 activity and decreases mitochondrial viability. Conclusion: Although more studies are required, we provide important proof of concept for RIPK1 inhibition leading to distinctive outcomes in lean and steatotic liver undergoing IRI. Considering the rising incidence of nonalcoholic fatty liver disease (NAFLD) in the general population, it will be imperative to address this critical difference when treating patients with RIPK1 inhibitors. This study also presents a new target for drug therapy to prevent hepatocellular injury in NAFLD.

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Solvent-based formulations for intravenous mouse pharmacokinetic studies: tolerability and recommended solvent dose limits

Cited by 38 publications

References 11 publications

The pharmaceutical solvent N-methyl-2-pyrollidone (NMP) attenuates inflammation through Krüppel-like factor 2 activation to reduce atherogenesis

The pharmaceutical solvent N-methyl-2-pyrollidone (NMP) attenuates inflammation through Krüppel-like factor 2 activation to reduce atherogenesis

In vivo use of the CYP inhibitor 1‐aminobenzotriazole to increase long‐term exposure in mice

Influence of Fat on Differential Receptor Interacting Serine/Threonine Protein Kinase 1 Activity Leading to Apoptotic Cell Death in Murine Liver Ischemia Reperfusion Injury Through Caspase 8

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