Absorption, distribution, and excretion of DJ-927, a novel orally effective taxane, in mice, dogs, and monkeys.
DJ-927, currently undergoing Phase I clinical trial, is a new orally effective taxane with potent antitumor effects. The absorption, tissue distribution, and excretion of DJ-927 were investigated in mice, dogs, and monkeys after a single oral administration. After oral administration of [14C]DJ-927, radioactivity was rapidly absorbed, with the Cmax occurring within 1-2 h in all species. The blood and plasma radioactivity elimination was biphasic and species-dependent. Elimination half-life of plasma in dogs was much longer than those in monkeys or mice. In mice, radioactivity was rapidly distributed to all tissues except for the central nervous system, especially to adrenal glands, liver, pituitary glands, kidneys, lungs, and spleen. In all species, radioactivity was mainly excreted in feces. Following a single oral administration to mice, more than 80% of the radioactivity was excreted within 48 h; in dogs and monkeys, 80% of the radioactivity was excreted within 168 h. Urinary excretion was less than 7% of radioactive dose in all species. In vitro plasma protein binding of [14C]DJ-927 in the mouse, dog, and monkey plasma ranged from 92-98%. These studies showed that, the novel oral taxane DJ-927 was rapidly absorbed in all three species when administered by the oral route. The long biological half-life and slow elimination of radioactivity were distinctive in particular, compared with commercial taxanes. DJ-927 (as parent compound and its metabolites) is widely distributed to tissues except the brain. These preclinical data are useful for the design of clinical trials of DJ-927 and also for their interpretation.
Ono
Chiho
C
Drug Metabolism & Physicochemical Property Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Kita-Kasai, Tokyo, Japan. onoch74g@daiichipharm.co.jp
Takao
Atsushi
A
Atsumi
Ryo
R
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D004285:Dogs; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D011485:Protein Binding; D013045:Species Specificity; D043823:Taxoids / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D013997:Time Factors; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D043823:Taxoids; C479543:tesetaxel