Author/Authors :
William J. Watkins، نويسنده , , Yakira Landaverry، نويسنده , , Roger Léger، نويسنده , , Renée Litman، نويسنده , , Thomas E. Renau، نويسنده , , Nicole Williams، نويسنده , , Rose Yen، نويسنده , , Jason Z. Zhang، نويسنده , , Suzanne Chamberland، نويسنده , , Deidre Madsen، نويسنده , , David Griffith، نويسنده , , Vrushali Tembe، نويسنده , , Keith Huie، نويسنده , , Michael N. Dudley، نويسنده ,
Abstract :
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.
