The Measurement of Partition Coefficients

Dearden, John C.; Bresnen, G. M.

doi:10.1002/qsar.19880070304

Cited by 241 publications

(186 citation statements)

References 29 publications

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“…Theoretical background concerning transbuccal penetration would indicate this pH value for buccal membrane. The p value falls within the proper range for potential drugs to penetrate the lipid phase of the buccal membrane (Dearden & Bresnen, 1988;Taylor, 1990;Earll, 1999;Yener et al, 2010).…”

Section: Lipophylicity Of Doxepinmentioning

confidence: 77%

Design, development and characterization of buccal bioadhesive films of Doxepin for treatment of odontalgia

et al. 2014

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Tricyclic antidepressants, as doxepin hydrochloride (DH), may have analgesic local effect due to its biochemical mechanism of action. Delivery of DH directly to the oral cavity could be an interesting alternative for toothache due to its analgesic local effect. One problem associated with the mucosal administration routes is the short residence time of the dosage form on the mucosal membranes. In this sense, we have developed new doxepin mucoadhesive films able of reducing pain and increasing the effectiveness of treatment. For this purpose, we tested three different polymers: chitosan, sodium hydroxypropylmethylcellulose (HPMC) and sodium carboxymethylcellulose (SCMC) in film elaboration. The results obtained show that all films are hydrophilic matrices that absorb water when placed in an aqueous media. All the films hydrated very quickly, reaching high percentage of swelling after just few minutes (5 min for SCMC, 2 min for HPMC and 30 min for chitosan). Moreover, the SCMC and HPMC films were dissolved whereas chitosan was not dissolved. Dissolution also leads to viscous liquids with a higher retention time over mucosal surfaces what may lead to adhesive interactions. In vitro permeation studies showed that for all the formulations studied, SCMC (19.91%), HPMC (69.5%) and chitosan (24.17%), the percentage of drug permeated increased compared to the drug solution (8.26%). Specifically the HPMC film presents greater amounts of doxepin permeated (49.27 ± 4.47 mg/cm 2 ).

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Section: Lipophylicity Of Doxepinmentioning

confidence: 77%

Design, development and characterization of buccal bioadhesive films of Doxepin for treatment of odontalgia

et al. 2014

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“…Other difficulties concerns compounds that can tautomerize or equilibrate between zwitterion and neutral form, and amphiphilic chemicals may behave as detergents. 56,57 [Braumann, 1986;Dearden and Bresnen, 1988]. …”

Section: Linear Relationship Between δG Lipocds and Log P (Experimenmentioning

confidence: 99%

The extravascular penetration of tirapazamine into tumours: a predictive model of the transport and efficacy of hypoxia specific cytotoxic analogues and the potential use of cucurbiturils to facilitate delivery

Fong¹

2017

IJCBDD

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To cite this version:Clifford Fong. The extravascular penetration of tirapazamine into tumours: a predictive model of the transport and efficacy of hypoxia specific cytotoxic analogues and the potential use of cucurbiturils to facilitate delivery. [Research Report] Eigenenergy. 2017, pp.2017 -2017 International Journal of Computational Biology and Drug Design: In press 2017 The extravascular penetration of tirapazamine into tumours: a predictive model of the transport and efficacy of hypoxia specific cytotoxic analogues and the potential use of cucurbiturils to facilitate delivery.Clifford W. Fong Eigenenergy, Adelaide, South Australia. AbstractA multiparameter model of the diffusion, antiproliferative assays IC 50 and aerobic and hypoxic clonogenic assays for a wide range of neutral and radical anion forms of tirapazamine (TPZ) analogues has found that: (a) extravascular diffusion is governed by the desolvation, lipophilicity, dipole moment and molecular volume, similar to passive and facilitated permeation through the blood brain barrier and other cellular membranes, (b) hypoxic assay properties of the TPZ analogues show dependencies on the electron affinity, as well as lipophilicity and dipole moment and desolvation, similar to other biological processes involving permeation of cellular membranes, including nuclear membranes, (c) aerobic properties are dependent on the almost exclusively on the electron affinity, consistent with electron transfer involving free radicals being dominant with little or no drug permeation of membranes, and most likely occurring in the extracellular matrix. Application of the model to the DNA binding equilibrium constants of TPZ analogues with acridine or acridine-like moieties show that ligand water desolvation and lipophilicity are the dominant processes governing the DNA intercalation of TPZ analogues. This conclusion is consistent with DFT modelling of the complexes formed by TPZ analogues with neutral and N-protonated acridine moieties which intercalate with the guanine DNA nucleobases.A quantum mechanical study has shown that TPZ can form stable complexes with cucurbit [7]uril as a precursor to proof of principle of improved TPZ delivery to tumours.Keywords: Tirapazamine analogues, intra-tumoural diffusion, anti-cancer, hypoxia, cytotoxicity, DNA binding, cucurbiturils, quantum mechanics Abbreviations Tirapazamine TPZ, free energy of water desolvation ΔG desolv,CDS , lipophilicity free energy ΔG lipo,CDS , cavity dispersion solvent structure of the first solvation shell CDS, multicellular layers MCL, extracellular matrix ECM, diffusion through support membrane D s , diffusion through multicellular layer D MCL , cucurbit[n]urils CB, cucurbit [7]urils, CB [7], highest occupied molecular orbital HOMO, lowest unoccupied molecular orbital LUMO, density functional molecular orbital theory DFT, adiabatic electron affinity AEA, cisplatin CisPt, ratio aerobic property:hypoxic property HCR, aerobic aer, hypoxic hyp, DNA binding equilibrium constant K DNA, multiple correlation coeffici...

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“…Due to the wide range of their values, partition coefficients are usually quoted on a logarithmic scale, as log P. Shake-flask experiments and potentiometry are traditional methodologies used for determining partition coefficients in the standard water|n-octanol system [5][6][7][8][9]. However, the partition coefficients of ionised fractions of drugs were usually ignored.…”

Section: Determination Of Partition Coefficientsmentioning

confidence: 99%

Use of voltammetry for in vitro equilibrium and transport studies of ionisable drugs

et al. 2014

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In this review, we will briefly outline the voltammetric investigations of the transfer of ionisable drugs at the interface between two immiscible electrolyte solutions. The voltammetric techniques enable the determination of some key in vitro properties of ionisable drugs, including partition coefficient, diffusioncoefficient and membrane permeability. Some successful applications will be highlighted, together with the background methodologies.

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The Measurement of Partition Coefficients

Cited by 241 publications

References 29 publications

Design, development and characterization of buccal bioadhesive films of Doxepin for treatment of odontalgia

Design, development and characterization of buccal bioadhesive films of Doxepin for treatment of odontalgia

The extravascular penetration of tirapazamine into tumours: a predictive model of the transport and efficacy of hypoxia specific cytotoxic analogues and the potential use of cucurbiturils to facilitate delivery

Use of voltammetry for in vitro equilibrium and transport studies of ionisable drugs

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