In vivo efficacy of XR9051, a potent modulator of P-glycoprotein mediated multidrug resistance

Overexpression of P-glycoprotein (P-gp) is a potential cause of multidrug r esistance (MDR) in tumours. We have previously reported that XR9051 (N-(4-( 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z, 6Z) -6-benzylidene-1-methyl-2,5-dioxo-3-. piperazinylidene)methylbenzamide) is a potent and specific inhibitor of P-gp, which reverses drug resistance in several murine and human MDR cell lines. In this study we have evaluated th e in vivo efficacy of this novel modulator in a panel of murine and human t umour models and examined its pharmacokinetic profile. Efficacy studies in mice bearing MDR syngeneic tumours (P388/DX Johnson, MC26) or human tumour xenografts (A2780AD, CH1/DOXr, H69/LX) demonstrated that co-administration of XR9051 significantly potentiated the anti-tumour activity of a range of cytotoxic drugs. This modulatory activity was observed following parenteral and oral co-administration of XR9051. In addition, the combination schedul es were well-tolerated. Following intravenous administration in mice, XR905 1 is rapidly distributed and accumulates in tumours and other tissues. In a ddition, the compound is well-absorbed after oral administration. These dat a suggest that XR9051 has the potential for reversing clinical MDR mediated by P-glycoprotien.