title: Pharmacokinetics and Urinary Excretion Mechanism of Orteronel (TAK-700), A Novel 17,20-Lyase Inhibitor, in Animals.
abstract: Orteronel is newly identified as a selective 17,20-lyase inhibitor for an agent for castration resistant prostate cancer. The absorption and disposition of [(14)C]orteronel were investigated in rats and monkeys. Orteronel was extensively excreted into rat and monkey urine in an unchanged form after oral administration. The unbound based renal clearances in rats and monkeys were greater than the respective glomerular filtration rates (GFR), suggesting that urinary tubular secretion plays an important role in the renal excretion of orteronel. Therefore, the uptake of [(14)C]orteronel was investigated using rat kidney slices to estimate the contribution of carrier-mediated transport on the urinary tubular secretion. The uptake study using rat kidney slices suggested that the transport of orteronel from the blood circulation to the kidney was mediated by a digoxin sensitive transport system represented by Oatp4c1 and non-saturable components. Furthermore, the saturable component accounted for a limited fraction of the total renal uptake by rat kidney slices. These results suggested that non-saturable uptake mainly contributed to the renal excretion of orteronel in rats.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Goto
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Moriya
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Mandai
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tagawa
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Asahi
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000652:urine*; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000652:urine*; D007668:Kidney / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D009281:Naphthalenes / Q000493:pharmacokinetics* / Q000652:urine*; D011485:Protein Binding; D051381:Rats
chemical_list: D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009281:Naphthalenes; C571806:orteronel