RT Journal Article SR Electronic T1 NONLINEAR ORAL PHARMACOKINETICS OF THE α-ANTAGONIST 4-AMINO-5-(4-FLUOROPHENYL)-6,7-DIMETHOXY-2-[4-(MORPHOLINOCARBONYL)-PERHYDRO-1,4-DIAZEPIN-1-YL]QUINOLINE IN HUMANS: USE OF PRECLINICAL DATA TO RATIONALIZE CLINICAL OBSERVATIONS JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 197 OP 204 DO 10.1124/dmd.32.2.197 VO 32 IS 2 A1 Anthony Harrison A1 Alison Betts A1 Katherine Fenner A1 Kevin Beaumont A1 Alan Edgington A1 Sarah Roffey A1 John Davis A1 Pierre Comby A1 Paul Morgan YR 2004 UL http://dmd.aspetjournals.org/content/32/2/197.abstract AB 4-Amino-5-(4-fluorophenyl)-6,7-dimethoxy-2-[4-(morpholinocarbonyl)-perhydro-1,4-diazepin-1-yl]quinoline (UK-294,315) is an antagonist of the human α1-adrenoceptor and exhibits nonlinear oral pharmacokinetics in humans. Superproportional increases in Cmax occur (220-fold, over a 1- to 50-mg dose range), area under the curve increases linearly, but time to maximum concentration decreases with dose, suggesting variation in rate but not extent of absorption. Oral absorption in humans is extensive, with only 14% of an orally administered (20 mg) radiolabeled dose excreted unchanged in the feces. In rats and dogs, UK-294,315 is partially eliminated as unchanged drug in feces (29 and 14% of an intravenous dose, respectively). Oral bioavailability is low in rats (11%) and high in dogs (71%), in keeping with systemic clearance. Fecal elimination of unchanged drug was 60% after oral administration to rats, indicating incomplete absorption in this species, whereas absorption in dogs is complete. UK-294,315 is a P-glycoprotein (P-gp) substrate (Km, 15 μM) exhibiting polarized flux in Caco-2 cell monolayers, saturable across a concentration range of 5 to 200 μM. Furthermore, the observations in vitro occurred at similar concentrations to those estimated in the gut lumen in clinical trials (dose range, 1-100 mg). It is considered that P-gp acts as a saturable absorption barrier to UK-294,315, slowing the rate of absorption at low doses, and is responsible for the observed nonlinearity in oral disposition in humans. Rat and dog pharmacokinetic studies offered limited insight into the process(es) driving nonlinear pharmacokinetics in humans. Our current understanding of the functional effects of P-gp in the human intestine, in combination with in vitro studies at clinically relevant concentrations, has helped rationalize the clinical data for UK-294,315. The American Society for Pharmacology and Experimental Therapeutics