title: Multiple pathways are involved in the oral absorption of BMS-262084, a tryptase inhibitor, in rats: role of paracellular transport, binding to trypsin, and P-glycoprotein efflux.
abstract: BMS-262084 is a potent and selective beta-lactam tryptase inhibitor with therapeutic potential for treating asthma. The oral bioavailability of BMS-262084 was low in rats (4% at a dose of 0.5 mg/kg) due to poor absorption. BMS-262084 was excreted mainly unchanged in the urine, suggesting minimal metabolism in rats. The objective of this study was to investigate the mechanisms of oral absorption of BMS-262084 in rats. Modulation of intestinal tight junctions, binding to trypsin, and involvement of the intestinal dipeptide transport system and P-glycoprotein (P-gp) in the absorption of BMS-262084 were examined. Coadministration of BMS-262084 with SQ-29852, a substrate of the intestinal dipeptide transport system, did not change the oral absorption of BMS-262084. An increase in the dose of BMS-262084 from 0.5 to 50 mg/kg resulted in a 3.7-fold increase in its oral absorption. Inulin absorption was enhanced upon coadministration with BMS-262084, suggesting the opening of tight junctions in the intestinal epithelium. Coadministration of aprotinin, a trypsin inhibitor, increased the oral absorption of BMS-262084 several fold. In vitro, using Caco-2 cells, BMS-262084 appeared to be a P-gp substrate, with an efflux ratio of 14. These results suggest that absorption of BMS-262084 is mediated by several concurrent mechanisms. At higher doses of BMS-262084, increased absorption may be primarily due to opening of tight junctions in the intestinal epithelium and consequent absorption via the paracellular pathway, while at lower doses, binding to trypsin may contribute to limiting its absorption. P-gp efflux may also play a role in influencing the absorption of BMS-262084. The intestinal dipeptide transporter system does not appear to be involved in the absorption of BMS-262084.
authors.affiliation: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543, USA. amrita.kamath@bms.com
authors.forename: Amrita V
authors.initials: AV
authors.lastname: Kamath
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morrison
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Harper
authors.forename: Shih-Jung
authors.initials: SJ
authors.lastname: Lan
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Marino
authors.forename: Saeho
authors.initials: S
authors.lastname: Chong
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D018938:Caco-2 Cells; D004151:Dipeptides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007004:Hypoglycemic Agents; D007269:Injections, Intra-Arterial; D007328:Insulin; D007408:Intestinal Absorption; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects; D014357:Trypsin / Q000378:metabolism*; D053802:Tryptases
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001384:Azetidines; C467955:BMS-262084; D004151:Dipeptides; D007004:Hypoglycemic Agents; D007328:Insulin; D010879:Piperazines; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D014357:Trypsin; C509223:Tpsab1 protein, rat; C509221:Tpsb2 protein, rat; D053802:Tryptases