Calculated Molecular Properties and Multivariate Statistical Analysis in Absorption Prediction

Norinder, Ulf; Haeberlein, Markus

doi:10.1002/3527601473.ch16

Cited by 9 publications

(4 citation statements)

References 27 publications

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“…Increasing the concentration of solubilized drug in the GI fluids will affect the concentration gradient across the intestinal membrane and thereby possibly the rate and extent of absorption. 2 For poorly water-soluble drugs, surfactants represent a very commonly used type of excipient. In general, surfactants increase the drug absorption by increasing the concentration of solubilized drug in the GI tract, by increasing the apparent drug solubility and/or the dissolution rate.…”

Section: ■ Introductionmentioning

confidence: 99%

“…For poorly water-soluble drugs, which at present are the majority of small molecules in development for oral administration, one way of improving drug absorption is to facilitate the solubilization of the drug in the gastrointestinal (GI) fluids. Increasing the concentration of solubilized drug in the GI fluids will affect the concentration gradient across the intestinal membrane and thereby possibly the rate and extent of absorption . For poorly water-soluble drugs, surfactants represent a very commonly used type of excipient.…”

Section: Introductionmentioning

confidence: 99%

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Kolliphor Surfactants Affect Solubilization and Bioavailability of Fenofibrate. Studies of in Vitro Digestion and Absorption in Rats

et al. 2015

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Selection of excipients for drug formulations requires both intellectual and experimental considerations as many of the used excipients are affected by physiological factors, e.g., they may be digested by pancreatic enzymes in the gastrointestinal tract. In the present paper we have looked systematically into the differences between Kolliphor ELP, EL, and RH40 and how they affect the bioavailability of fenofibrate, through pharmacokinetic studies in rats and in vitro lipolysis studies. The study design was made as simple as possible to avoid confounding factors, for which reason the tested formulations only comprised an aqueous micellar solution of the model drug (fenofibrate) in varying concentrations (2-25% (w/v)) of the three tested surfactants. Increased concentrations of Kolliphor ELP and EL led to increased fenofibrate AUC0-24h values. For the Kolliphor RH40 formulations, an apparent fenofibrate absorption optimum was seen at 15% (w/v) surfactant, displaying both the highest AUC0-24h and Cmax. The reduced absorption of fenofibrate from the formulation containing the highest level of surfactant (25% w/v) was thought to be caused by some degree of trapping within Kolliphor RH40 micelles. In vitro, Kolliphor ELP and EL were found to be more prone to digestion than Kolliphor RH40, though not affecting the in vivo results. The highest fenofibrate bioavailability was attained from formulations with high Kolliphor ELP/EL levels (25% (w/v)), indicating that these surfactants are the better choice for solubilizing fenofibrate in order to increase the absorption upon oral administration. Due to drug dependent effects of the different types of Kolliphor, more studies are recommended in order to understand which type of Kolliphor is best suited for a given drug.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kolliphor Surfactants Affect Solubilization and Bioavailability of Fenofibrate. Studies of in Vitro Digestion and Absorption in Rats

et al. 2015

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“…Yes/No, Positive/Negative), three [24] (high with F > 80 %; moderate with F = 21-79 %, and low with F < 20 %), or four groups [25] (1: < 20 %, 2: 20-49 %; 3: 50-79 %; 4: > 80 %).…”

Section: Prognosis Of Bioavailabilitymentioning

confidence: 99%

Quantitative Structure-Property Relationship Analysis of Drugs’ Pharmacokinetics Within the Framework of Biopharmaceutics Classification System Using Simplex Representation of Molecular Structure

Golovenko

Borisyuk

Kulinskiy

et al. 2014

Challenges and Advances in Computational Chemistry and Physics

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The Biopharmaceutics Classification System (BCS) categorizes drugs into one of four biopharmaceutical classes according to their water solubility and membrane permeability characteristics and broadly allows the prediction of the rate-limiting step in the intestinal absorption process following oral administration. When combined with the in vitro dissolution characteristics of the drug product, the BCS takes into account three major factors: solubility, intestinal permeability, and dissolution rate, all of which govern the rate and extent of oral drug absorption from immediate-release (IR) solid oral-dosage forms. The concept of BCS provides a better understanding of the relationship between drug release from the product and the absorption process. This report reviews the current status of computational tools in predicting the base properties (aqueous solubility, and passive absorption) of the BCS and explores the application of the Simplex representation of molecular structure (SiRMS) QSAR approach in absorption (bioavailability) research. The main advantages of SiRMS are consideration of the different physico-chemical properties of atoms, high robustness, predictivity, and interpretability of developed models that creates good opportunities for molecular design. The reliability of developed QSAR models as predictive virtual screening tools and their utility for targeted drug design were validated by subsequent synthetic and biological experiments. The SiRMS approach was implemented as "HiT QSAR" software. In addition, we provide our perspective on the progress of research into an in silico equivalent to the BCS.

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“…A further possible simplifi cation using only the number of H -bond forming atoms and PLS statistics was proposed [35] . Excellent correlations of PSA with the number of H -bond donors and acceptors were published [35,36] . Obviously, PSA, like N a and N d , is not a perfect descriptor for transport properties, at least in the framework of the initial defi nition.…”

Section: Surface H -Bond Descriptorsmentioning

confidence: 99%

H‐Bonding Parameterization in Quantitative Structure–Activity Relationships and Drug Design

Raevsky

2007

Methods and Principles in Medicinal Chemistry

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Calculated Molecular Properties and Multivariate Statistical Analysis in Absorption Prediction

Cited by 9 publications

References 27 publications

Kolliphor Surfactants Affect Solubilization and Bioavailability of Fenofibrate. Studies of in Vitro Digestion and Absorption in Rats

Kolliphor Surfactants Affect Solubilization and Bioavailability of Fenofibrate. Studies of in Vitro Digestion and Absorption in Rats

Quantitative Structure-Property Relationship Analysis of Drugs’ Pharmacokinetics Within the Framework of Biopharmaceutics Classification System Using Simplex Representation of Molecular Structure

H‐Bonding Parameterization in Quantitative Structure–Activity Relationships and Drug Design

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