RESUMO
We hypothesised that Hansen Solubility Parameters (HSPs) can be used to predict drug-nail affinities. Our aims were to: (i) determine the HSPs (δD, δP, δH) of the nail plate, the hoof membrane (a model for the nail plate), and of the drugs terbinafine HCl, amorolfine HCl, ciclopirox olamine and efinaconazole, by measuring their swelling/solubility in organic liquids, (ii) predict nail-drug interactions by comparing drug and nail HSPs, and (iii) evaluate the accuracy of these predictions using literature reports of experimentally-determined affinities of these drugs for keratin, the main constituent of the nail plate and hoof. Many solvents caused no change in the mass of nail plates, a few solvents deswelled the nail, while others swelled the nail to varying extents. Fingernail and toenail HSPs were almost the same, while hoof HSPs were similar, except for a slightly lower δP. High nail-terbinafine HCl, nail-amorolfine HCl and nail-ciclopirox olamine affinities, and low nail-efinaconazole affinities were then predicted, and found to accurately match experimental reports of these drugs' affinities to keratin. We therefore propose that drug and nail Hansen Solubility Parameters may be used to predict drug-nail interactions, and that these results can assist in the design of drugs for the treatment of nail diseases, such as onychomycosis and psoriasis. To our knowledge, this is the first report of the application of HSPs in ungual research.
Assuntos
Unhas/efeitos dos fármacos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Adolescente , Adulto , Antifúngicos/administração & dosagem , Ciclopirox , Interações Medicamentosas , Feminino , Humanos , Queratinas/metabolismo , Masculino , Pessoa de Meia-Idade , Morfolinas/farmacologia , Doenças da Unha/tratamento farmacológico , Doenças da Unha/metabolismo , Doenças da Unha/microbiologia , Unhas/metabolismo , Naftalenos/farmacologia , Onicomicose/tratamento farmacológico , Onicomicose/metabolismo , Piridonas/farmacologia , Solubilidade , Terbinafina , Triazóis/farmacologia , Adulto JovemRESUMO
No disponible
Assuntos
Humanos , Úlcera de Buruli/metabolismo , Hanseníase Virchowiana/genética , Hanseníase Virchowiana/transmissão , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Organização Mundial da Saúde/organização & administração , Úlcera de Buruli/congênito , Hanseníase Virchowiana/metabolismo , Hanseníase Virchowiana/patologia , Dermatopatias/diagnóstico , Dermatopatias/patologia , Preparações Farmacêuticas/análise , Rifampina/administração & dosagem , Rifampina/metabolismoRESUMO
No disponible
Assuntos
Humanos , Masculino , Feminino , Hanseníase/tratamento farmacológico , Preparações Farmacêuticas/metabolismo , Rifampina/uso terapêutico , Triancinolona/uso terapêutico , Hanseníase Paucibacilar/tratamento farmacológico , Penicilinas/uso terapêutico , Tratamento Biológico/métodos , Dexametasona/uso terapêutico , Quimioterapia Combinada , Imunoterapia , Hanseníase Tuberculoide/tratamento farmacológico , Sulfonas/uso terapêutico , Clofazimina/uso terapêutico , Corticosteroides/uso terapêutico , Talidomida/uso terapêutico , Antialérgicos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Antipiréticos/uso terapêutico , Analgésicos/uso terapêutico , Bicarbonato de Sódio/uso terapêuticoAssuntos
Dermatopatias/classificação , Pele/metabolismo , Administração Tópica , Animais , Carcinoma Basocelular/patologia , Fármacos Dermatológicos/metabolismo , Humanos , Hanseníase/metabolismo , Hanseníase/patologia , Neoplasias Induzidas por Radiação/patologia , Preparações Farmacêuticas/metabolismo , Ratos , Neoplasias Cutâneas/patologia , Raios UltravioletaRESUMO
2-arylpropionic acid derivatives are probably the most frequently cited drugs exhibiting the phenomenon that is best known as chiral inversion. One enantiomer of drug is converted into its antipode either in the presence of a solvent or more often in inner environment of an organism. Mechanistic studies of the metabolic chiral inversion were carried out for several drugs from NSAIDs, and a model of this inversion was suggested and subsequently confirmed. The chiral inversion of NSAIDs has been intensively studied in the context of the pharmacological and toxicological consequences. However, the group of NSAIDs is not the sole group of drugs in which the inversion phenomenon can be observed. There exist several other drugs that also display chiral inversion of one or even both of their enantiomers. These drugs belong to different pharmacotherapeutic groups as monoamine oxidase inhibitors, antiepileptic drugs, drugs used in the treatment of hyperlipoproteinemia or drugs that are effective in the treatment of leprosy. Moreover, some chiral or prochiral drugs are metabolized to give chiral metabolites that undergo chiral inversion too, which can have direct impact on pharmacological properties or toxicity of the drug. As the process of chiral inversion is affected by several factors, so the intensity of chiral inversion of individual substances and at different conditions can differ considerably. Interspecies differences and types of tissue are reported to be the main factors that were recognized to play the key role in the process of chiral inversion. Some of more recent studies have revealed that several other factors, such as the route of administration or interaction with other xenobiotics, can influence the enantiomeric conversion, too. Chiral inversion does not seem to be a phenomenon connected with only several drugs from some unique group of 2-arylpropionic acid derivatives: it is also observed in drugs with rather different chemical structures and is much more frequent than it can be realized.
Assuntos
Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Animais , Humanos , Conformação Molecular , Preparações Farmacêuticas/administração & dosagem , Especificidade da Espécie , Estereoisomerismo , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologiaRESUMO
PURPOSE: The purpose of this study was the classification and identification of drug binding sites on albumins from several species in order to understand species differences of both drug binding properties and drug interaction on protein binding. METHODS: Binding properties and types of drug-drug interaction on the different albumins were examined using typical site I binding drugs, warfarin (WF) and phenylbutazone (PBZ), and site II binding drugs, ibuprofen (IP) and diazepam (DZ) on human albumin. Equilibrium dialysis was carried out for two drugs and the free concentrations of drugs were then treated using the methods of Kragh-Hansen (Mol. Pharmacol. 34. 160-171, (1988)). RESULTS: Binding affinities of site I drugs to bovine, rabbit and rat albumins were reasonably similar to human albumin. However, interestingly, those to dog albumin were considerably smaller than human albumin. On the other hand, binding parameters of DZ to bovine, rabbit and rat albumins were apparently different from those of human albumin. These differences are best explained by microenvironmental changes in the binding sites resulting from change of size and/or hydrophobicity of the binding pocket, rather than a variation in amino acid residues. CONCLUSIONS. We will propose herein that mammalian serum albumins used in this study contain specific drug binding sites: Rabbit and rat albumins contain a drug binding site, corresponding to site I on human albumin, and dog albumin contains a specific drug binding site corresponding to site II on the human albumin molecule.
Assuntos
Preparações Farmacêuticas/metabolismo , Albumina Sérica/metabolismo , Animais , Sítios de Ligação , Bovinos , Diazepam/metabolismo , Cães , Humanos , Ibuprofeno/metabolismo , Fenilbutazona/metabolismo , Ligação Proteica , Coelhos , Ratos , Albumina Sérica/isolamento & purificação , Varfarina/metabolismoRESUMO
There is ample evidence that the human acetylator phenotypes are associated with drug induced phenomena. It is principally the slow acetylators who exhibit toxic adverse effects because of their relative inability to detoxify the original drug compounds. In rare instances, however, it is the rapid acetylators who are at a disadvantage. In the matter of association of spontaneous disease with either acetylator phenotype, there are two groups of disorders to consider. First, disorders in which carcinogenic amines are known to be an aetiological factor. This is because these amines are substrates for the polymorphic N-acetyltransferase activity and hence there is a possible rational basis for searching for an association. Secondly, other disorders where searches for associations are based more on hunches. In the first group there is a definite statistical association between cancer of the bladder and the slow acetylator phenotype. In prevalence studies the slow phenotype is 39% more associated with bladder cancer than is the rapid phenotype. On the basis of the evidence now available it is not possible to say whether this association is because slow acetylators develop the disease more frequently or whether they survive longer. In the second group the relevant studies show (1) a greatly increased prevalence of slow acetylators in Gilbert's disease; (2) a confirmed association between the rapid acetylator phenotype and diabetes; (3) a possible association between the rapid acetylator phenotype and breast cancer; (4) a possible association between the slow acetylator phenotype and leprosy in Chinese patients; (5) an earlier age of onset of thyrotoxicosis (Graves' disease) in slow acetylators than in rapid acetylators; (6) no evidence of an association between either phenotype and spontaneous systemic lupus erythematosus.