title: Pharmacokinetics, mass balance, and tissue distribution of a novel DNA alkylating agent, VNP40101M, in rat.
abstract: VNP40101M (1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(2 methylamino)carbonyl] hydrazine), a novel DNA alkylating agent, is currently under clinical development for the treatment of cancer in Phase I clinical trials. This study investigated the pharmacokinetics, mass balance, and tissue distribution of [14C]-VNP40101M in rats following a single intravenous dose of 10 mg/kg. After 7 days, the total recovery of radioactivity was 85% for males and 79% for females. Most of the radioactivity was eliminated within 48 hours through urine (70%), with less excreted in feces (6%). Tissue contained relatively high radioactive residues with the highest concentrations in kidneys, liver, lung, and spleen. After 7 days, tissue still contained 9% of the dose. At both 5 minutes and 1 hour post-dose, brain contained relatively high radioactivity (5.9 and 3.3 micro g equivalence/g and 50% and 30% of the blood concentration, respectively), suggesting that VNP40101M penetrated the blood-brain barrier. The elimination half-life of VNP40101M was approximately 20 minutes, the peak plasma concentration (Cmax) averaged 11.3 micro g/mL, the volume of distribution (Vss) averaged 0.91 L/kg, and the total body clearance (Cl) averaged 33.5 mL/min/kg. The metabolite profile in urine was complex, indicating VNP40101M was extensively metabolized. There were no apparent sex differences in pharmacokinetic parameters of VNP40101M in the rat.
authors.affiliation: Development, Vion Pharmaceuticals, Inc, Four Science Park, New Haven, CT 06511, USA. jmao@vionpharm.com
authors.forename: John
authors.initials: J
authors.lastname: Mao
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Diana
authors.initials: D
authors.lastname: Wu
authors.forename: Bijan
authors.initials: B
authors.lastname: Almassain
mesh_terms: D000477:Alkylating Agents / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D006834:Hydrazines / Q000097:blood / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: C424963:1,2-bis(methylsulfonyl),1-(2-chloroethyl)-2-(methylamino)carbonylhydrazine; D000477:Alkylating Agents; D006834:Hydrazines