Abstract
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.
Footnotes
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↵1 Abbreviations used are: UK-294,315, 4-amino-5-(4-fluorophenyl)-6,7-dimethoxy-2-[4-(morpholinocarbonyl)-perhydro-1,4-diazepin-1-yl]quinoline; P-gp, P-glycoprotein; UK-298,108, 4-amino-5-(4-chlorophenyl)-6,7-dimethoxy-2-[4-(morpholinocarbonyl)-perhydro-1,4-diazepin-1-yl]quinoline; CP-100,356, [4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-quinazolin-2-yl]-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine; HPLC, high-performance liquid chromatography; kel, terminal elimination rate constant; AUC0-T, area under the plasma concentration-time curve; AUC0-∞, area under the plasma concentration-time curve, extrapolated to infinity; HBSS, Hanks' balanced salt solution; A-B, apical to basolateral; B-A, basolateral to apical;Papp, apparent permeability;Tmax, time to maximum concentration.
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↵2 In this laboratory, the P-gp substrate talinolol exhibits an A-B flux of <1 and B-A flux of 13 × 10-6 cm/s across Caco-2 cells at a substrate concentration of 25 μM.
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↵3 Estimated from dose dissolved in a combination of dose solution volume (250 ml) and upper gastrointestinal tract fluid volume (120-350 ml; taken from Dressman et al., 1998). Maximum concentration is calculated from the dose solution alone.
- Received April 14, 2003.
- Accepted October 1, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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