XR9576 is a novel inhibitor of P-glycoprotein (P-gp) that has been shown to reverse P-gp-dependent multidrug-resistance in tumor cell lines and tumor-bearing animals. Here we report the first i. v. and p. o. administration to healthy volunteers of XR9576 in dose-escalating studies with the aim of investigating its effects on safety, its pharmacokinetics, and a surrogate marker of efficacy. XR9576 was administered as a single dose-upward titration of 0. 1, 0. 2, 0. 5, 1. 0, and 2 mg/kg XR9576 i. v. or 50, 100, 200, 500, and 750 mg/volunteer p. o. The surrogate marker for in vivo efficacy examined the accumulation of the P-gp substrate Rhodamine-123 (Rh-123) in P-gp-expressing CD56+ lymphocytes by flow cytometry. Addition of Rh-123 to blood samples from subjects given XR9576 or a placebo demonstrated drug-dependent modulation of P-gp activity. Even at the lowest doses, significant effects were observed on Rh-123 accumulation in CD56+ cells VSports手机版. Maximal effects were seen during the i. v. infusion or 4-6 h after oral administration. As the dose was increased, a concomitant rise in the level and duration of P-gp blockade was observed. A dose of 2. 0 mg/kg i. v. and > or = 200 mg/volunteer p. o. gave approximately 100% inhibition of P-gp for in excess of 24 h. All doses of XR9576 were well tolerated. Inhibition increased with XR9576 plasma concentration, and maximal activity was achieved at 150-200 ng/ml XR9576. In conclusion, XR9576 has demonstrated sustained inhibition of P-gp after i. v. and oral administration and, supported by the elimination half-life of about 24 h, XR9576 is being taken into Phase II as a once-daily agent. .