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Biotech / Medical : Kosan BioSciences -- KOSN -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (496)	10/3/2004 4:29:28 PM
From: tuck	Respond to of 933

[Kinetics and mechanism of degradation of epothilone-D: An experimental anticancer agent] J Pharm Sci. 2004 Sep 30;93(12):2953-2961. [Epub ahead of print] Kinetics and mechanism of degradation of epothilone-D: An experimental anticancer agent. Jumaa M, Carlson B, Chimilio L, Silchenko S, Stella VJ. Department of Pharmaceutical Chemistry, University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047. The objective of this study was to investigate the stability and the degradation pathway of epothilone-D (Epo-D), an experimental anticancer agent. In pH range 4-9, Epo-D displayed pH-independent stability and the highest stability was observed at pH 1.5-2 where its thiazole group is protonated. Increasing the pH >9 or <1.5 resulted in an increase in the degradation rate. Epo-D contains an ester group that can be hydrolyzed. The formation of the hydrolytic product was confirmed by the nuclear magnetic resonance (NMR), fast atom bombardment mass spectroscopy and liquid chromatography/mass spectroscopy/mass spectroscopy techniques. The largely sigmoidal pH-rate profile is not consistent with the normal pH dependency of ester hydrolysis involving an addition/elimination mechanism. Hence, a hydrolysis mechanism through a carbonium ion was suggested. At pH 4 and 7.4, no buffer catalysis was observed (0.01, 0.02, and 0.05 M buffers) and no significant deuterium kinetic solvent isotope effect was noted. The degradation was very sensitive to changes in the dielectric constant of the solvents as significant enhancement in the stability was observed in buffer-acetonitrile and 0.1 M (SBE)(7m)-beta-cyclodextrin solutions compared with just buffer, suggesting that the rate-determining step in the degradation pathway involved formation of a polar transition state. Mass spectral analysis of the reaction run in (18)O water was consistent with incorporation of the (18)O in the alcohol hydroxyl rather than the carboxylate group. These observations strongly support the carbonium ion mechanism for the hydrolysis of Epo-D in the pH range 4-9. A pK(a) value of 2.86 for Epo-D was estimated from the fit of the pH-rate profile. This number was confirmed independently by the changes in ultraviolet absorbance of Epo-D as a function of pH (pK(a) 3.1) determined at 25 degrees C and the same ionic strength.<< Cheers, Tuck

To: scaram(o)uche who wrote (496)	10/27/2004 1:01:13 PM
From: tuck	Respond to of 933

[Population pharmacokinetic analysis of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) in adult patients with advanced malignancies] >>Cancer Chemother Pharmacol. 2004 Oct 19 [Epub ahead of print] Population pharmacokinetic analysis of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) in adult patients with advanced malignancies. Chen X, Bies RR, Ramanathan RK, Zuhowski EG, Trump DL, Egorin MJ. Department of Medical Oncology and Hematology, Princess Margaret Hospital, Room 5-221A, 610 University Ave., M5G 2M9, Toronto, ON, Canada. PURPOSE. 17-(Allylamino)-17-demethoxygeldanamycin (17AAG) is a novel anticancer agent in clinical development. The objectives of this study were to develop a population pharmacokinetic model for 17AAG and its major metabolite, 17AG, and to investigate influences of patient characteristics and biochemical markers on pharmacokinetic parameters estimated for 17AAG and 17AG. EXPERIMENTAL DESIGN. In a phase I clinical study, 17AAG was administered by intravenous infusion to 43 patients with refractory, advanced malignancies. Plasma concentrations of 17AAG and 17AG were determined by high-performance liquid chromatography. Plasma concentration vs time data were modeled using NONMEM. Nine covariates (age, sex, performance status, weight, height, body surface area, AST, bilirubin and serum creatinine) were investigated for their influences on individual pharmacokinetic parameters. RESULTS. Plasma concentration vs time data were best described by a two-compartment model for 17AAG and a one-compartment model for 17AG. Volumes of distribution were 24.2 and 89.6 l for 17AAG. Total elimination clearances were 26.7 and 21.3 l/h for 17AAG and 17AG, respectively. Both fixed and random effects pharmacokinetic parameters were well estimated. None of the covariates explained the interindividual variability in 17AAG and 17AG pharmacokinetic parameters or improved the fit of the model based on objective function changes. CONCLUSIONS. A population pharmacokinetic model was developed to describe 17AAG and 17AG population pharmacokinetic parameters and interindividual variabilities. There were substantial interindividual variabilities in 17AAG and 17AG pharmacokinetic parameters despite BSA-normalized dosing.<< Emphasis mine. Potential problem here? Cheers, Tuck