Apparent absolute oral bioavailability in excess of 100% for a vitronectin receptor antagonist (SB-265123) in rat. II. Studies implicating transporter-mediated intestinal secretion.
1. Transporters have been increasingly identified as a factor in limiting the oral bioavailability of certain drugs. Previously, the present authors investigated a compound (SB-265123) with an apparent absolute oral bioavailability (Fapp) consistently > 100%, and excluded likely artefactual causes for this observation, as well as standard considerations of non-stationary or non-linear pharmacokinetics. The data led the authors to believe that SB-265123 might be a transporter substrate in the rat, and it was hypothesized that transporter interactions might be responsible for the observed Fapp > 100%. 2. In the present study, a model was proposed incorporating rapid and complete absorption and elimination by a saturable intestinal secretory pathway. Intestinal secretion was demonstrated for SB-265123 using a rat single-pass intestinal perfusion technique. In addition, in a study employing both independent and simultaneous intravenous and oral administration of SB-265123, exposure to SB-265123 was greater than additive on joint intravenous and oral administration, lending further support to the hypothesis of a saturable transporter. Furthermore, in a study with co-administration of GF120918A, a transporter inhibitor, the observed Fapp for SB-265123 was only 84 +/- 17%, providing additional evidence for transporter involvement in the >100% Fapp phenomenon. 3. Experience with SB-265123 illustrates a counterintuitive impact of transporters on oral bioavailability and highlights the importance of considering transporter interactions in the systemic disposition of xenobiotics, even those not demonstrating low oral bioavailability.
Preclinical Drug Discovery, Cardiovascular & Urogenital Center of Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA 19406, USA. keith_w_ward@gsk
K W
KW
Ward
L B
LB
Hardy
J R
JR
Kehler
L M
LM
Azzarano
B R
BR
Smith
D000085:Acetates / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D000818:Animals; D016477:Artifacts; D001682:Biological Availability; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D051381:Rats
D000085:Acetates; D000631:Aminopyridines; D039302:Integrin alphaVbeta3; D026901:Membrane Transport Proteins; C121647:SB 265123