[Pharmacokinetics, tissue distribution and metabolism of IPI-504, a novel water-soluble Hsp90 inhibitor. A comparison with 17-AAG]
>>2005 AAPS Annual Meeting and Exposition 11/5/2005 - 11/10/2005
Pharmacokinetics, tissue distribution and metabolism of IPI-504, a novel water-soluble Hsp90 inhibitor. A comparison with 17-AAG.
Tracks: Contributed Papers: Preclinical PK/PD
Date/Time: Tuesday, November 08, 2005
1:00 PM - 5:00 PM
Location: T3311
Description:
Purpose To study the pharmacokinetics, tissue distribution and metabolism of IPI-504 and 17-AAG in rats, cynomolgus monkeys and tumor-bearing mice. Methods IPI-504 or 17-AAG were administered intravenously to mice, rats, and monkeys. Plasma and tissue were collected and quenched with antioxidant-containing acidic quench buffers to preserve the hydroquinone, IPI-504. Samples were analyzed by LC-MS/MS to quantitate IPI-504, 17-AAG and the major metabolite 17-AG. In vitro metabolism studies were performed by incubation of IPI-504 or 17-AAG in human, rat and cynomolgus monkey liver microsomes and determination of the metabolic profile by HPLC-UV and LC-MS. Results IPI-504 is the hydrochloride salt of the hydroquinone of 17-AAG. We observed that IPI-504 and 17-AAG interconvert in vitro in liver microsomes and tumor cells with identical metabolic profiles. The interconversion is due to IPI-504 oxidation and 17-AAG enzymatic reduction. The same interconversion was observed in vivo after IPI-504 or 17-AAG administration in mice (tumor-bearing), rats, and monkeys leading to similar pharmacokinetic and tissue distribution profiles for IPI-504, 17-AAG and 17-AG in all species. Quantitatively, the combined concentrations of IPI-504 and 17-AAG indicate a higher exposure in the rat versus cynomolgus monkey with a Cmax/Dose and an AUC0-8/Dose of 105 nM/mg/m2 and 97 nM.h/mg/m2, respectively, in the rat versus 44 nM/mg/m2 and 41 nM.h/mg/m2, respectively, in the monkey. Higher exposure in the rat is further supported by tissue distribution data showing a combined concentration of IPI-504, 17-AAG and 17-AG in rat liver of 32.5 µg/g versus 0.6 µg/g in the monkey 6 h after administration of 300 mg/m2 IPI-504. In tumor-bearing mice, IPI-504, 17-AAG and 17-AG were rapidly cleared from plasma within 1-2 hours, but are selectively retained for up to 48 hours in tumor tissue at pharmacologically active concentrations. Conclusion IPI-504 and 17-AAG have similar pharmacokinetic and metabolic profiles due to the hydroquinone-quinone interconversion of both compounds.
Speakers:
Author
Dr. Julian Adams
Infinity Pharmaceuticals
Author
Dr. John A. Barrett
Infinity Pharmaceuticals
Author
Dr. Jebecka Hudak
Infinity Pharmaceuticals
Author
Dr. Vito J. Palombella
Infinity Pharmaceuticals
Author
Dr. Christine Pien
Infinity Pharmaceuticals
Author
Dr. Jens R. Sydor
Infinity Pharmaceuticals
Author
Dr. Jens R. Sydor
Infinity Pharmaceuticals
Author
Dr. Jeffrey K. Tong
Infinity Pharmaceuticals
Author
Dr. Caroline Woodward
Infinity Pharmaceuticals
Author
Dr. Yilong Zhang
Infinity Pharmaceuticals <<
Appears the solubility advantage is the only one they've got. Of course, it might be a pretty significant advantage . . .
Cheers, Tuck |
