RESUMO
PURPOSE: Polymeric drugs, including patiromer (Veltassa®), bind target molecules or ions in the gut, allowing fecal elimination. Non-absorbed insoluble polymers, like patiromer, avoid common systemic drug-drug interactions (DDIs). However, the potential for DDI via polymer binding to orally administered drugs during transit of the gastrointestinal tract remains. Here we elucidate the properties correlated with drug-patiromer binding using quantitative structure-property relationship (QSPR) models. METHODS: We selected 28 drugs to evaluate for binding to patiromer in vitro over a range of pH and ionic conditions intended to mimic the gut environment. Using this in vitro data, we developed QSPR models using step-wise linear regression and analyzed over 100 physiochemical drug descriptors. RESULTS: Four descriptors emerged that account for ~70% of patiromer-drug binding in vitro: the computed surface area of hydrogen bond accepting atoms, ionization potential, electron affinity, and lipophilicity (R 2 = 0.7, Q 2 = 0.6). Further, certain molecular properties are shared by nonbinding, weak, or strong binding compounds. CONCLUSIONS: These findings offer insight into drivers of in vitro binding to patiromer and describe a useful approach for assessing potential drug-binding risk of investigational polymeric drugs.
Assuntos
Modelos Biológicos , Pesquisa Farmacêutica/métodos , Polímeros/farmacologia , Relação Quantitativa Estrutura-Atividade , Administração Oral , Simulação por Computador , Interações Medicamentosas , Trânsito Gastrointestinal , Interações Hidrofóbicas e Hidrofílicas , Modelos Lineares , Estrutura Molecular , Polímeros/químicaRESUMO
Hyperkalemia is a potentially life-threatening condition, and patients who have chronic kidney disease, who are diabetic, or who are taking renin-angiotensin-aldosterone system inhibitors are at increased risk. Therapeutic options for hyperkalemia tend to have limited effectiveness and can be associated with serious side effects. Colonic potassium secretion can increase to compensate when urinary potassium excretion decreases in patients with renal impairment, but this adaptation is insufficient and hyperkalemia still results. Patiromer is a novel, spherical, nonabsorbed polymer designed to bind and remove potassium, primarily in the colon, thereby decreasing serum potassium in patients with hyperkalemia. Patiromer has been found to decrease serum potassium in patients with hyperkalemia having chronic kidney disease who were on renin-angiotensin-aldosterone system inhibitors. Results of nonclinical studies and an early phase clinical study are reported here. Two studies with radiolabeled drug, one in rats and the other in dogs, confirmed that patiromer was not absorbed into the systemic circulation. Results of an in vitro study showed that patiromer was able to bind 8.5 to 8.8 mEq of potassium per gram of polymer at a pH similar to that found in the colon and had a much higher potassium-binding capacity compared with other resins, including polystyrene sulfonate. In a study in hyperkalemic rats, a decrease in serum potassium was observed via an increase in fecal potassium excretion. In a clinical study in healthy adult volunteers, a significant increase in fecal potassium excretion and a significant decrease in urinary potassium excretion were observed. Overall, patiromer is a high-capacity potassium binder, and the chemical and physical characteristics of patiromer may lead to good clinical efficacy, tolerability, and patient acceptance.
Assuntos
Quelantes/uso terapêutico , Hiperpotassemia/tratamento farmacológico , Polímeros/uso terapêutico , Potássio/sangue , Animais , Biomarcadores/sangue , Quelantes/efeitos adversos , Quelantes/farmacocinética , Colo/efeitos dos fármacos , Colo/metabolismo , Modelos Animais de Doenças , Fezes/química , Humanos , Hiperpotassemia/sangue , Hiperpotassemia/diagnóstico , Eliminação Intestinal , Polímeros/efeitos adversos , Polímeros/farmacocinética , Resultado do TratamentoRESUMO
Further structure-activity relationships of a novel series of fungal efflux pump inhibitors with respect to potentiation of the activity of fluconazole against strains of C. albicans and C. glabrata over-expressing ABC-type efflux pumps are systematically explored. Rat protein binding and pharmacokinetics of selected analogues are reported.
Assuntos
Antifúngicos/farmacologia , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Piperazinas/química , Quinazolinonas/farmacologia , Soro/química , Animais , Antifúngicos/sangue , Antifúngicos/química , Antifúngicos/farmacocinética , Candida albicans/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Estrutura Molecular , Piperazina , Quinazolinonas/sangue , Quinazolinonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Following the optimization of diamine-containing efflux pump inhibitors with respect to in vitro potentiation activity, in vivo stability and acute toxicity, we addressed the question of how to control the pharmacokinetic properties of the series. Upon intravenous administration in the rat, tissue levels of MC-04,124 (the lead compound) were high and prolonged compared to those in the serum. The lipophilicity and basicity of analogues of this compound were systematically varied, and effects on potency and pharmacokinetics explored. The ratio of drug levels in tissue versus serum was not significantly reduced in any of the active analogues examined.
Assuntos
Anti-Infecciosos/farmacocinética , Transporte Biológico Ativo/efeitos dos fármacos , Diaminas/farmacocinética , Plasma/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/farmacologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Diaminas/administração & dosagem , Diaminas/farmacologia , Infusões Intravenosas , Metabolismo dos Lipídeos , Masculino , Testes de Sensibilidade Microbiana , Ofloxacino/metabolismo , Ofloxacino/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
The discovery of a series of quinazolinone-based fungal efflux pump inhibitors by high-throughput screening for potentiation of fluconazole in C. albicans is described. Attempts to improve the aqueous solubility of screening hits led to the discovery of an analog with greatly improved physical properties and activity against clinically-relevant Candida spp.
Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antifúngicos/síntese química , Candida/efeitos dos fármacos , Proteínas Fúngicas/antagonistas & inibidores , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Piperazinas/síntese química , Quinazolinas/síntese química , Antifúngicos/farmacologia , Candida/enzimologia , Farmacorresistência Fúngica , Sinergismo Farmacológico , Fluconazol/química , Fluconazol/farmacologia , Humanos , Técnicas In Vitro , Modelos Moleculares , Piperazinas/química , Piperazinas/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Solubilidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Structure-activity relationships of a novel series of fungal efflux pump inhibitors with respect to potentiation of the activity of fluconazole against strains of Candida albicans and Candida glabrata over-expressing ABC-type efflux pumps are systematically explored.
Assuntos
Antifúngicos/síntese química , Candida/efeitos dos fármacos , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Piperazinas/síntese química , Quinazolinas/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Candida/enzimologia , Candida albicans/efeitos dos fármacos , Candida albicans/enzimologia , Candida glabrata/efeitos dos fármacos , Candida glabrata/enzimologia , Farmacorresistência Fúngica , Sinergismo Farmacológico , Fluconazol/química , Fluconazol/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Humanos , Testes de Sensibilidade Microbiana , Piperazinas/química , Piperazinas/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Conformational restriction of the ornithine residue of the efflux pump inhibitor D-ornithine-D-homophenylalanine-3-aminoquinoline (MC-02,595, 2) furnished bioisosteric proline derivatives that were less toxic in vivo and as active as the lead in potentiating the activity of the fluoroquinolone levofloxacin via the inhibition of efflux pumps in Pseudomonas aeruginosa.