Accurate automated logPo/w measurement by gradient-flow liquid–liquid partition chromatography

Demare, Sandrine; Slater, Bryan; Lacombe, Gaëlle; Breuzin, Delphine; Dini, C.

doi:10.1016/j.chroma.2007.09.093

Cited by 11 publications

(5 citation statements)

References 20 publications

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“…Since the reported log P oct values are 2.6 for FT (15) and 2.2-2.3 for NT (33,34), respectively, FT has not only higher hydrophobicity but also higher lipophilicity than NT. Therefore, if these drugs are encapsulated in LNE particles, FT should show a higher EE% value than NT.…”

Section: Calculated K P Valuesmentioning

confidence: 99%

19F Nuclear Magnetic Resonance Spectrometric Determination of the Partition Coefficients of Flutamide and Nilutamide (Antiprostate Cancer Drugs) in a Lipid Nano-Emulsion and Prediction of Its Encapsulation Efficiency for the Drugs

et al. 2016

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Abstract. To design a useful lipid drug carrier having a high encapsulation efficiency (EE%) for the antiprostate cancer drugs flutamide (FT) and nilutamide (NT), a lipid nano-emulsion (LNE) was prepared with soybean oil (SO), phosphatidylcholine (PC), and sodium palmitate, and the partition coefficients (K p s) of the drugs for the LNE were determined by 19 F nuclear magnetic resonance (NMR) spectrometry. The 19 F NMR signal of the trifluoromethyl group of both drugs showed a downfield shift from an internal standard (trifluoroethanol) and broadening according to the increase in the lipid concentration due to their interaction with LNE particles. The difference in the chemical shift (Δδ) of each drug caused by the addition of LNE was measured under different amounts of LNE, and the K p values were calculated from the Δδ values. The results showed that FT has higher lipophilicity than NT. The total lipid concentration (SO + PC) required to encapsulate each drug into LNE with an EE% of more than 95% was calculated from the K p values as 93.3 and 189.9 mmol/L for FT and NT, respectively. For an LNE prepared with the total lipid concentration of 215 mmol/L, the predicted EE% values were 98 and 96% for FT and NT, respectively, while the experimental EE% values determined by a centrifugation method were approximately 99% for both drugs. Thus, the 19 F NMR spectrometric method is a useful technique to obtain the K p values of fluorinated drugs and thereby predict the theoretical lipid concentrations and prepare LNEs with high EE% values.

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Section: Calculated K P Valuesmentioning

confidence: 99%

19F Nuclear Magnetic Resonance Spectrometric Determination of the Partition Coefficients of Flutamide and Nilutamide (Antiprostate Cancer Drugs) in a Lipid Nano-Emulsion and Prediction of Its Encapsulation Efficiency for the Drugs

et al. 2016

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“…Rejection of PPCP is based on charge interaction of PPCP (pKa values) and membrane, MWCO, and hydrophobicity interactions [25]. Hydrophobicity of PPCPs is measured by log P value where P is defined as the ratio of the concentrations of a solute in octonol to that in water [30]. PPCPs rejections presented in Table 4 are explained using these mechanisms below.…”

Section: Rejection Of Pharmaceuticals and Personal Care Productsmentioning

confidence: 99%

Use of nanofiltration and reverse osmosis in reclaiming micro-filtered biologically treated sewage effluent for irrigation

et al. 2015

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Nanofiltration (NF) pre-treatment reduced reverse osmosis (RO) membrane fouling.• Permeate blends of RO after NF treatment and NF only are suitable for irrigation.• NF or RO, alone removed most pharmaceuticals and personnel care products (PPCPs).• PPCPs removals by NF membranes were lower than those by RO membranes. a b s t r a c tMicro-filtered, biologically treated sewage effluent (BTSE) generally has high sodium adsorption ratio (SAR) and sodium (Na) and chloride (Cl) concentrations. Therefore it cannot be directly used for irrigating sensitive crops. A study was conducted on a micro-filtered BTSE from a Sydney water treatment plant to determine whether the BTSE can be treated using nanofiltration (NF) and reverse osmosis (RO) to bring these risk parameters within safety limits. The study showed that using NF and RO alone could not produce the required ratio of SAR. Furthermore, NF alone did not remove the necessary levels of Na and Cl ions while RO did. However, blending equal proportions of NF permeate and RO permeate obtained from a two stages hybrid treatment system consisting of NF followed by RO resulted in a product quality suitable for irrigation in terms of the above mentioned risk factors. Utilizing NF prior to RO reduced the RO membrane fouling as well. Both NF and RO removed most of the pharmaceutical and personal care products from the feed water and this may subsequently protect soil and ground water from potential hazards.

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“…They predicted that poor absorption or permeation into cells for a molecule is more likely when the number of hydrogen‐bond donors > 5, the number of hydrogen‐bond acceptors > 10, the relative molecular mass > 500 and the calculated log P (cLog P ) > 5. This last in particular is a measure of lipophilicity, and those who design chemical libraries will always seek molecules that obey the Ro5, including through experimental measurements of the partition coefficient log P and/or the distribution coefficient log D . Note, however, that natural product‐based drugs (still a major source of leads and indeed marketed drugs; see below) very rarely, if ever, obey the Ro5 and, indeed, even some synthetic drugs have very large molecular weights ; for example, navitoclax dihydrochloride , a Bcl‐2 inhibitor, has seven ring systems and a relative molecular mass of 1047.5.…”

Section: Drug Biophysics and The Rule‐of‐5mentioning

confidence: 99%

Finding novel pharmaceuticals in the systems biology era using multiple effective drug targets, phenotypic screening and knowledge of transporters: where drug discovery went wrong and how to fix it

Kell

2013

The FEBS Journal

105

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Despite the sequencing of the human genome, the rate of innovative and successful drug discovery in the pharmaceutical industry has continued to decrease. Leaving aside regulatory matters, the fundamental and interlinked intellectual issues proposed to be largely responsible for this are: (a) the move from 'function-first' to 'target-first' methods of screening and drug discovery; (b) the belief that successful drugs should and do interact solely with single, individual targets, despite natural evolution's selection for biochemical networks that are robust to individual parameter changes; (c) an over-reliance on the rule-of-5 to constrain biophysical and chemical properties of drug libraries; (d) the general abandoning of natural products that do not obey the rule-of-5; (e) an incorrect belief that drugs diffuse passively into (and presumably out of) cells across the bilayers portions of membranes, according to their lipophilicity; (f) a widespread failure to recognize the overwhelmingly important role of proteinaceous transporters, as well as their expression profiles, in determining drug distribution in and between different tissues and individual patients; and (g) the general failure to use engineering principles to model biology in parallel with performing 'wet' experiments, such that 'what if?' experiments can be performed in silico to assess the likely success of any strategy. These facts/ideas are illustrated with a reasonably extensive literature review. Success in turning round drug discovery consequently requires: (a) decent systems biology models of human biochemical networks; (b) the use of these (iteratively with experiments) to model how drugs need to interact with multiple targets to have substantive effects on the phenotype; (c) the adoption of polypharmacology and/or cocktails of drugs as a desirable goal in itself; (d) the incorporation of drug transporters into systems biology models, en route to full and multiscale systems biology models that incorporate drug absorption, distribution, metabolism and excretion; (e) a return to 'function-first' or phenotypic screening; and (f) novel methods for inferring modes of action by measuring the properties on system variables at all levels of the 'omes. Such a strategy offers the opportunity of achieving a state where we can hope to predict biological processes and the effect of pharmaceutical agents upon them. Consequently, this should both lower attrition rates and raise the rates of discovery of effective drugs substantially.

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Accurate automated logPo/w measurement by gradient-flow liquid–liquid partition chromatography

Cited by 11 publications

References 20 publications

19F Nuclear Magnetic Resonance Spectrometric Determination of the Partition Coefficients of Flutamide and Nilutamide (Antiprostate Cancer Drugs) in a Lipid Nano-Emulsion and Prediction of Its Encapsulation Efficiency for the Drugs

19F Nuclear Magnetic Resonance Spectrometric Determination of the Partition Coefficients of Flutamide and Nilutamide (Antiprostate Cancer Drugs) in a Lipid Nano-Emulsion and Prediction of Its Encapsulation Efficiency for the Drugs

Use of nanofiltration and reverse osmosis in reclaiming micro-filtered biologically treated sewage effluent for irrigation

Finding novel pharmaceuticals in the systems biology era using multiple effective drug targets, phenotypic screening and knowledge of transporters: where drug discovery went wrong and how to fix it

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