title: ADME characterization in rats revealed immediate secretion of AZD7903 into the stomach after IV dosing.
abstract: The distribution of AZD7903 and/or its metabolites was studied in rats following a single p.o. or i.v. dose using quantitative whole-body autoradiography (QWBA). At 5 min after i.v. administration of the ¹⁴C compound, high levels of radioactivity were observed in the fundus of the stomach compared to blood and plasma and the rest of the stomach, indicating an active secretion of ¹⁴C material into the stomach. Also, excretion and pharmacokinetics were studied following p.o. and i.v. dosage in rats. The radioactivity was mainly excreted via feces, and even in i.v. administered bile-duct cannulated (BDC) animals a significant part of radioactivity (26% in males and 57% in females) was recovered in the feces in the form of parent compound and two minor metabolic products. The compound was well absorbed (F% 98 in males and 76 in females), and showed low clearance in plasma (0.14 L/h/kg in males and 0.03 L/h/kg in females) and low-intermediate Vd(ss) (0.7 L/kg). Clear differences in metabolic pathways (qualitative) and rates (quantitative) and consequently in PK parameters between sexes were observed. In summary, the results indicate AZD7903 being substrate for a transporter protein and support the hypothesis that the differences in disposition between sexes are due to differences in metabolic pathways and rates.
authors: CNS&Pain iMed Science Södertälje, AstraZeneca Research and Development, Södertälje, Sweden. Johanna.Haglund@bredband.net
authors: J
authors: J
authors: Haglund
authors: N
authors: N
authors: Borg
mesh_terms: D000042:Absorption; D061605:Administration, Intravenous; D000818:Animals; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism*; D006827:Hydantoins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007700:Kinetics; D008297:Male; D051381:Rats; D012737:Sex Factors; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors
chemical_list: C587766:1'-(3-(3,4-dichlorophenyl)prop-2-en-1-yl)-2H,5H-spiro(imidazolidine-4,3'-indole)-2,2',5(1'H)-trione; D006827:Hydantoins; D007211:Indoles; D050916:TRPV Cation Channels