Clinical and in-vitro investigations to assess transporter based drug interaction potential of a partial alpha agonist R450

doi:doi:10.1016/j.clpt.2004.12.214

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Clinical Pharmacology & Therapeutics (2005) 77, P84–P84; doi: 10.1016/j.clpt.2004.12.214

Clinical and in-vitro investigations to assess transporter based drug interaction potential of a partial alpha agonist R450

S. E. Bellibas MD¹, D. Schwab PhD¹, B. Liu MD¹, E. Gaudeul-Ehrhart MD¹, P. Weigl BS¹ and A. Dorr¹

¹Hoffmann-La Roche Inc., XIQ Inc., Nutley, NJ

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Abstract

Since R450 is a compound actively secreted by kidneys with a renal clearance (CL_R) exceeding normal GFR; it was decided to be investigated further for exact mechanism of excretion and assess DDI potential based on any possible active transporters.

First, a clinical study was performed on 12 healthy female subjects aged 40–65 years using cimetidine and probenecid as probe drugs for cationic and anionic transport mechanisms at renal tubular level. While probenecid had no effect, cimetidine caused a statistically significant change in exposure by reducing CL_R from 11.8 L/hr to 8.7 L/hr.

Furthermore, in cell-line study, the bi-directional transport of R450 in wild-type LLC-PK1 cells was inhibited by verapamil, while no inhibition was observed by a P-gp specific inhibitor although caused partly inhibition in P-gp transfected cells (human MDR1, mouse mdr1a). A complete inhibition was observed in P-gp transfected LLC-PK1 cells using verapamil as an inhibitor suggesting R450 is a weak substrate for P-gp and also mediated by multiple transporters.

Based on these observations it was concluded that R450 was a substrate for mainly organic cationic transporters in addition to possible other multiple transporters including P-gp with a lesser degree.