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 mdr1a(-/-) and wildtype mice. Transport experiments in Caco-2 monolayers at low concentrations (<10 microM) showed that the secretory flux of [(14)C]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. Mdr1a(-/-) 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 [(3)H]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 mdr1a(-/-) 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 [(14)C]apafant (54.9%) exceeded biliary excretion (26.5%). However, in mdr1a(-/-) 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 mdr1a(-/-) mice. The conclusions were: (1) apafant and digoxin are P-gp substrates, and (2) absence of mdr1a encoded P-gp significantly alters tissue distribution (especially in brain) and excretion routes (biliary and intestinal) of apafant.
Leusch
Andreas
A
Boehringer Ingelheim Pharma KG, Department of Pharmacokinetics and Drug Metabolism, 88397, Biberach/Riss, Germany. andreas.leusch@bc.boehringer-ingelheim.com
Volz
Astrid
A
Müller
Gabriele
G
Wagner
Andrea
A
Sauer
Achim
A
Greischel
Andreas
A
Roth
Willy
W
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency* / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D019540:Area Under Curve; D001381:Azepines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001652:Bile Ducts / Q000378:metabolism; D018938:Caco-2 Cells / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014018:Tissue Distribution / Q000502:physiology; D014230:Triazoles / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D001381:Azepines; D002250:Carbon Radioisotopes; D010972:Platelet Activating Factor; D014230:Triazoles; C052518:WEB 2086; C095122:multidrug resistance protein 3