scholarly journals Prediction of Biopharmaceutical Drug Disposition Classification System (BDDCS) by Structural Parameters

2019 ◽  
Vol 22 ◽  
pp. 247-269 ◽  
Author(s):  
Yeganeh Golfar ◽  
Ali Shayanfar
Keyword(s):  
Classification System ◽  
Drug Disposition ◽  
Structural Parameters ◽  
Log P ◽  
Metabolizing Enzymes ◽  
Acceptable Accuracy ◽  
Water Partition Coefficient ◽  
Pharmacokinetic Properties ◽  
Solvation Parameters ◽  
External Test

Modeling of physicochemical and pharmacokinetic properties is important for the prediction and mechanism characterization in drug discovery and development. Biopharmaceutics Drug Disposition Classification System (BDDCS) is a four-class system based on solubility and metabolism. This system is employed to delineate the role of transporters in pharmacokinetics and their interaction with metabolizing enzymes. It further anticipates drug disposition and potential drug-drug interactions in the liver and intestine. According to BDDCS, drugs are classified into four groups in terms of the extent of metabolism and solubility (high and low). In this study, structural parameters of drugs were used to develop classification-based models for the prediction of BDDCS class. Reported BDDCS data of drugs were collected from the literature, and structural descriptors (Abraham solvation parameters and octanol–water partition coefficient (log P)) were calculated by ACD/Labs software. Data were divided into training and test sets. Classification-based models were then used to predict the class of each drug in BDDCS system using structural parameters and the validity of the established models was evaluated by an external test set. The results of this study showed that log P and Abraham solvation parameters are able to predict the class of solubility and metabolism in BDDCS system with good accuracy. Based on the developed methods for prediction solubility and metabolism class, BDDCS could be predicted in the correct with an acceptable accuracy. Structural properties of drugs, i.e. logP and Abraham solvation parameters (polarizability, hydrogen bonding acidity and basicity), are capable of estimating the class of solubility and metabolism with an acceptable accuracy.

Interaction of cisplatin anticancer drug with C20 bowl: DFT investigation

2021 ◽  
pp. 1-12
Author(s):  
Reza Ghiasi ◽  
Alireza Valizadeh
Keyword(s):  
Drug Interaction ◽  
Charge Transfer ◽  
Anticancer Drug ◽  
Structural Parameters ◽  
Orbital Energy ◽  
Molecular Volume ◽  
Log P ◽  
Water Partition Coefficient ◽  
The Stability ◽  
Precursor Molecules

This study investigated the cisplatin (anticancer drug) interaction with C20 bowl and C20H10(Bowl) molecule including hydrogen-saturated with using mPW1PW91 functional. The stability of the various isomers of drug interaction with C20 bowl was investigated. The interaction energy values were estimated in these systems. Changes in the structural parameters and the frontier orbital energy and HOMO-LUMO gap values were evaluated. Charge transfer between fragments were shown with electrophilicity-based charge transfer (ECT). The Octanol–water partition coefficient (log P) and molecular volume (Vm) of these drug precursor molecules were studied. Also, Pt-C bond characterizations were illustrated using QTAIM analysis. The results showed that C20 bowl can be a promising nanocarrier for cisplatin anticancer drug.

Relationships between Cellular Toxicity, the Maximum Tolerated Dose, Lipophilicity and Electrophilicity

1992 ◽  
Vol 20 (4) ◽  
pp. 549-562
Author(s):  
Herbert S. Rosenkranz ◽  
Edwin J. Matthews ◽  
Gilles Klopman
Keyword(s):  
Cultured Cells ◽  
Chemical Properties ◽  
Maximum Tolerated Dose ◽  
Log P ◽  
Lumo Energy ◽  
Cellular Toxicity ◽  
Water Partition Coefficient ◽  
The Us ◽  
Lowest Unoccupied Molecular Orbital ◽  
Rats And Mice

Results on cellular toxicity and maximum tolerated dose (MTD) for rats and mice were available for approximately 175 chemicals tested by the US National Toxicology Program. Additionally, the computed log P (log octanol-water partition coefficient) and the lowest unoccupied molecular orbital (LUMO) energy values, a measure of electrophilicity were also available for most of these chemicals. Analysis of the chemicals on the basis of their physical and quantum chemical properties and their toxic effects on cultured cells and rodents showed that: 1) as a group, the more toxic chemicals showed a trend towards higher LUMO energies (i.e. less electrophilic); 2) cytotoxic chemicals exhibited increased lipophilicity; and 3) cytotoxic chemicals were associated with increased systemic toxicity (as measured by the MTD). None of these relationships was expressed in a significant linear fashion as a function of the concentration at which the chemicals exhibited cytotoxicity.

scholarly journals QSAR of caffeines by similarity cluster prediction

2014 ◽  
Vol 12 (3) ◽  
pp. 365-376 ◽  
Author(s):  
Teodora Harsa ◽  
Alexandra Harsa ◽  
Beata Szefler
Keyword(s):  
Predictive Model ◽  
Log P ◽  
Test Set ◽  
Pubchem Database ◽  
External Test

AbstractA novel QSAR approach based on correlation weighting and alignment over a hypermolecule that mimics the investigated correlational space was performed on a set of 40 caffeines downloaded from the PubChem database. The best models describing log P and LD50 values of this set of caffeine derivatives were validated against the external test set and in a new predictive model by using clusters of similarity.

Apparent octanol/water partition coefficients of pentachlorophenol as a function of pH

1982 ◽  
Vol 60 (16) ◽  
pp. 2104-2106 ◽  
Author(s):  
Klaus L. E. Kaiser ◽  
Ilze Valdmanis
Keyword(s):  
Aqueous Solution ◽  
Ionic Strength ◽  
Partition Coefficient ◽  
Linear Function ◽  
Partition Coefficients ◽  
Extreme Values ◽  
Log P ◽  
Water Partition Coefficient ◽  
Non Linear ◽  
Good Agreement

The apparent 1-octanol/water partition coefficient (log PApp) of pentachlorophenol (PCP) varies in non-linear function with pH of the aqueous solution. In the range of pH 1.2 to 13.5 extreme values of log PApp 4.84 at pH 1.2 and log PApp 1.3 at pH 10.5 were observed. In the alkaline regime, log PApp increases strongly with the ionic strength. The ion-corrected partition coefficient of PCP was found to be log P 5.05 in good agreement with literature values.

Determination of Ionization Constant (pKa) and Octanol–Water Partition Coefficient (Log P) of Cyclopiazonic Acid

2005 ◽  
Vol 88 (5) ◽  
pp. 1367-1370 ◽  
Author(s):  
Victor S Sobolev
Keyword(s):  
Partition Coefficient ◽  
Potentiometric Titration ◽  
Ionization Constant ◽  
Cyclopiazonic Acid ◽  
Log P ◽  
Experimental Conditions ◽  
Water Partition Coefficient

Abstract The ionization constant (pKa) and the octanol–water partition coefficient (log P) of the important mycotoxin cyclopiazonic acid (CPA) were determined by means of potentiometric titration, and the lipophilicity profile (log D) was calculated. Under the experimental conditions, pKa of CPA = 2.97 ± 0.09, log P = 3.83 ± 0.10, and log D at pH 7.4 = −0.58.

Structure–Toxicity Relationships for the Fathead Minnow, Pimephales promelas: Narcotic Industrial Chemicals

1983 ◽  
Vol 40 (6) ◽  
pp. 743-748 ◽  
Author(s):  
Gilman D. Veith ◽  
Daniel J. Call ◽  
L. T. Brooke
Keyword(s):  
Fathead Minnow ◽  
Pimephales Promelas ◽  
Chemical Activity ◽  
Alkyl Halides ◽  
Log P ◽  
Industrial Chemicals ◽  
Water Partition Coefficient ◽  
The Common ◽  
Structure Toxicity Relationship ◽  
Toxicity Relationship

Narcosis is a reversible state of arrested activity of protoplasmic structures caused by a wide variety of organic chemicals. This nonspecific mode of toxic action was found predominant in acute toxicity studies of industrial chemicals and fish. This paper presents 96-h LC50 values for 65 industrial chemicals including alcohols, ketones, ethers, alkyl halides, and substituted benzenes. The common mode of action permitted the development of a structure–toxicity relationship as follows: log LC50 = −0.94 log P + 0.94 log (0.000068P + 1) −1.25 where P is the n-octanol/water partition coefficient. The data show that the toxicity of the chemicals to fish is directly comparable with the toxicity in mammals when expressed as chemical activity.

A pharmacogenetic study of docetaxel and thalidomide in patients with androgen-independent prostate cancer (AIPC) using targeted human DMET genotyping platform

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3580-3580
Author(s):  
J. F. Deeken ◽  
T. Cormier ◽  
D. K. Price ◽  
S. Steinberg ◽  
K. Tran ◽  
...  
Keyword(s):  
Clinical Response ◽  
Phase Ii ◽  
Drug Disposition ◽  
Individual Variability ◽  
Response To Therapy ◽  
Drug Metabolizing Enzymes ◽  
Nucleotide Polymorphisms ◽  
Pharmacogenetic Study ◽  
Metabolizing Enzymes ◽  
Genotyping Platform

3580 Background: Pharmacogenetic research holds the promise of individualizing cancer therapy by reducing inter-individual variability in drug response, thus enhancing efficacy and reducing toxicity. Past research has been limited due to the lack of a robust genotyping platform that can screen for single nucleotide polymorphisms (SNPs) in the dozens of genes known to be involved in drug disposition. We pilot tested the new Affymetrix Targeted Human Drug Metabolizing Enzymes and Transporter (DMET) 1.0 panel in an exploratory study of docetaxel and thalidomide. The DMET 1.0 panel tests for 1,229 genetic variations in 169 drug disposition genes, including 49 CYP450 genes, 73 non-CYP genes, and 47 transporters. Methods: DNA samples from 47 patients with AIPC enrolled in a randomized phase II trial using docetaxel and thalidomide vs. docetaxel alone were genotyped using the DMET 1.0 panel. Patients’ response was determined using RECIST criteria. Toxicities were graded using the NCI-CTC, and patients were identified if they experienced grade 3 or 4 toxicity. Given the distinct side effect profiles of these two drugs, specific toxicities were assigned as being due to either docetaxel or thalidomide. An association between the SNP parameters and clinical response or toxicity was tested using Mehta’s modification to Fisher’s exact test. Reported results were limited to those where p<0.01. Results: Six SNPs in three genes were associated with response to therapy: PPAR-delta (p=0.0011), SULT1C2 (p=0.0083), and CHST3 (4 SNPs, p=0.0001 to 0.0034). For toxicities associated with docetaxel, five SNPs in three genes were identified: UGT1A1 (2 SNPs, p=0.0009 to 0.0094), UGT1A9 (2 SNPs, p=0.0016 to 0.0096), and CYP2A7 (p=0.0027). SNPs in CYP2B6 (p=0.0033), ABCC1 (p=0.0036), and ABCC6 (p=0.0075) were associated with toxicities from thalidomide. Conclusion: We identified nine genes in which SNPs were potentially significantly associated with clinical response and toxicity to treatment. These results highlight the important role that non-CYP450 and phase II drug metabolizing enzymes may play in the efficacy and disposition of docetaxel and thalidomide. Confirmatory studies are warranted. No significant financial relationships to disclose.

scholarly journals Molecular pharmacokinetic determinants of anticancer kinase inhibitors in humans

2011 ◽  
pp. 77-92
Author(s):  
Julie Scholler ◽  
Dominique Leveque
Keyword(s):  
Drug Interactions ◽  
Nuclear Receptors ◽  
Kinase Inhibitors ◽  
Drug Disposition ◽  
Clinical Impact ◽  
Published Data ◽  
Drug Metabolizing Enzymes ◽  
Orphan Nuclear Receptors ◽  
Metabolizing Enzymes ◽  
Molecular Determinants

This review presents the published data regarding the molecular determinants (drug metabolizing enzymes, drug transporters and orphan nuclear receptors) of approved anticancer kinase inhibitors pharmacokinetics in humans. The clinical impact of these determinants (drug disposition and drug–drug interactions) is also discussed.

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