Altered drug disposition of the platelet activating factor antagonist apafant in mdr1a knockout mice

The aim of the present study was to determine a potential impact of P-glycoprotein (P-gp) on the tissue distribution and disposition of apafant (WEB 2086, CAS 105219-56-5), a selective platelet-activating factor antagonist, and on digoxin in mdrla(-/-) and wildtype mice. Transport experiments in Caco-2 monolayers at low concentrations (<10 muM) showed that the secretory flux of [C-14]apafant and [3 H]digoxin exceeded the absorptive flux nine times. This efflux was concentration dependent and subject to inhibition by the P-gp substrates verapamil and cyclosporin A. This indicates that active drug transporter P-gp was involved in apafant and digoxin absorption. Mdrla(-/-) mice showed a more than 70-fold higher concentration of digoxin-related radioactivity (P<0.001) in the brain than wildtype mice after intravenous doses of 0.05 mg/kg [H-3]digoxin. Differences were less pronounced in other tissues. Both liquid scintillation counting and whole body autoradiography yielded comparable results and they also matched recently published data. Apafant-related radioactivity was about ten-fold higher in the brain of mdrla(-/-) mice compared to wildtype mice following intravenous doses of 2 mg/kg radiolabelled apafant. Only slight or negligible differences were observed in other tissues. In wildtype mice, intestinal excretion of [C-14]apafant (54.9%) exceeded biliary excretion (26.5%). However, in mdrla(-/-) mice biliary excretion (50.7%) exceeded intestinal excretion (6.8%). These differences were mirrored in the urinary and faecal excretion. Pharmacokinetic parameters of apafant and radioactivity did not differ between wildtype and mdrla(-/-) mice. The conclusions were: (1) apafant and digoxin are P-gp substrates, and (2) absence of mdrla encoded P-gp significantly alters tissue distribution (especially in brain) and excretion routes (biliary and intestinal) of apafant. (C) 2002 Elsevier Science B.V. All rights reserved.