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.
Ward
K W
KW
Preclinical Drug Discovery, Cardiovascular & Urogenital Center of Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA 19406, USA. keith_w_ward@gsk
Hardy
L B
LB
Kehler
J R
JR
Azzarano
L M
LM
Smith
B R
BR
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