Spearman correlation coefficients were calculated between changes of continuous

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 Spearman correlation coefficients were calculated between changes of continuous Empty Spearman correlation coefficients were calculated between changes of continuous

Post  jy9202 on Wed Apr 02, 2014 7:17 am

Clearance and distribution volume at the steady state were calculated from the primary parame ters. The plasma concentration versus time curves were calculated from the model derived parame ters, and the elimination half lives were calculated from the slope [You must be registered and logged in to see this link.] of the terminal elimination phase. Bone marrow data were derived after adjustment of concentrations to 109 cells, The pharmacokinetic modeling was performed using WinNonlin version 5. 2, Oral bioavailability defined as the fraction of the oral administered dose of CR8 that reaches the systemic circu lation was calculated according to the following formula: Linearity and limit of quantification The calibration curve was linear within the ranges of 0. 1 ug ml 10 ug ml, and had a correlation coefficient 0. 9987, The lower limit of quantification for CR8 was 0.

1 ug ml in human plasma. The [You must be registered and logged in to see this link.] precision and accuracy at LLOQ were 3. 7 and 13. 3%, respectively. Accuracy and precision The precision and accuracy between and within batch were always below 13% from the nominal values in all cases. Precision and accuracy fulfilled the standard guiding principles for validation of bioanalytical methods, i. e. Calculations and statistics The peak areas of CR8 were plotted versus the corre sponding nominal concentrations of the standards, and the standard curve was calculated by linear regression. CR8 concentrations in mouse plasma, organs and quality control samples were calculated from the resulting curves. All values are presented as mean S. D.

Results Analysis of CR8 A precise and accurate method [You must be registered and logged in to see this link.] was developed to detect the drug in plasma and tissue samples in order to investi gate the pharmacokinetics of CR8. CR8 is a lipophilic compound; however, due to the presence of the 2 pyridyl ring attached to the benzyl ring, its lipophilicity is lower than that of the parent analogue roscovitine. DMSO was found to be a suitable solvent for very high concentrations of CR8, and 50 mM HCl was found to be a suitable solv ent for standard concentrations. Protein precipitation is the simplest approach for removing most proteins from biological samples. Methanol was shown to be better than acetonitrile in deproteinizing the plasma and extracting CR8 due to lower number of interfering peaks. UV absorbance UV absorbance was determined by running a UV IVIS spectrum scan of CR8 dissolved in 50 mM HCl, No interference in the absorption range was detected.

The scan revealed good absorption in the UV 210 nm 310 nm wavelength ranges, and 305 nm was selected as the best measurement wavelength to ensure good selectiv ity and good sensitivity with a wide range of linear re sponse for construction of the standard curves. Chromatograms and specificity The CR8 retention time was around 5. 26 0. 3 min. Se lectivity was confirmed by the absence of significant interfering peaks from endogenous compounds in the blank plasma at this retention time, Also, no interference was found from endogenous compounds in the mouse plasma and tissue samples compared to con trol samples, 15% for QCs both between batches and within batches and 20% for LLOQ, No differences were observed between mouse and human plasma concerning concentrations in QCs, Recovery The absolute recovery of CR8 in plasma was 97 6%, 95 5.


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