Abstract
1. 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.
2. 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.
3. 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 Vdss (0.7 L/kg). Clear differences in metabolic pathways (qualitative) and rates (quantitative) and consequently in PK parameters between sexes were observed.
4. 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.
Acknowledgements
The authors thank Dr Gustav Ahlin for his contribution in the transporter area, Dr Katarina Nydahl for her contribution with data interpretation of the QWBA study and Dr Johan Sandell for the synthesis of the radio-labeled material.