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For identification and quantitation of oxycodone and its metabolites, a Waters Acquity ultra-performance liquid chromatographic (UPLC) system with an autosampler, a vacuum degasser, and a column oven was used. The analytical column used was a Waters BEH C18 (2. Mesalamine Delayed-Release Capsules (Delzicol)- FDA eluents were 0.

The flow rate was 0. A positive ionization mode of electrospray was used with a capillary voltage of 2800 V and a cone voltage of 60 V. W-mode ion optics and dynamic range enhancement (DRE) option were used. Aperture 1 voltages of 5 and 65 V were used to obtain molecular ion data and in-source fragment ion data, respectively. Hydrocodone Bitartrate and Pseudoephedrine Hydrochloride (Rezira)- FDA mass spectrometer and UPLC system were operated under Micromass MassLynx 4.

The real positives (metabolites) and their identifications were confirmed from the data manually. In quantitation, ion chromatograms with 50 mDa window were used. Correlation coefficient R2 was 0. For analysis of oxycodone samples from hepatocyte binding experiments, a Waters Alliance 2695 HPLC with a column oven and an autosampler was used together with Waters XBridge C18 (2.

Data was acquired using Waters Quattro Micro triple quadrupole mass spectrometer with z-spray electrospray ion source. A capillary voltage of 1400 V and cone voltage of 28 V were used.

Argon was used as a collision gas at 3. The subsequent samples from the well did not change the ratio of the incubation volume to the number of cells. In vitro clearance based on unbound drug concentration (in vitro CLu) was calculated by diving the apparent clearance by fuinc.

The weight and height of the donor was estimated to be the average value for particular age and gender (Kuczmarski et al.

The anatomical and physiological parameters were calculated using the procedures by Johnson et al. The body surface area (BSA) was calculated from the weight and height using the equation by Kirklin barratt boyes cardiac surgery et al.

The cardiac output was calculated Mesalamine Delayed-Release Capsules (Delzicol)- FDA children from BSA using the equation 3 in Johnson et Mesalamine Delayed-Release Capsules (Delzicol)- FDA. The liver volume (l) was calculated as 0.

Intrinsic in vivo clearance in the liver based on unbound drug concentration (CLuint,H) was obtained by multiplying intrinsic in vitro CLu with the total number of hepatocytes. The fraction unbound of oxycodone in plasma Mesalamine Delayed-Release Capsules (Delzicol)- FDA was estimated to be 0. The hepatic plasma clearance (CLH) of oxycodone was estimated using the well-stirred model (Yang et al.

All of these metabolites were observed in cells from 4-year-old donor and in pooled adult cells, whereas cells from 3 days, 2 and 5-months-old donors contained five to seven metabolites (Table 1).

No metabolites specific to a single age group only were observed. The detected metabolites were identified based on the mass spectral accurate mass and fragment ion data and retention times.

Due to low abundance of metabolites M1 and M3, fragment ion data was not observed and therefore only tentative identifications as changes in molecular formula with respect to oxycodone were obtained. Proposed in vitro metabolic pathway of oxycodone in hepatocyte incubations.

Qualitative metabolite profiles from hepatocyte incubations. Quantitative analytical results revealed that noroxycodone was a major metabolite in all Mesalamine Delayed-Release Capsules (Delzicol)- FDA batches (Figure 2). Ketoconazole reduced but not completely blocked the conversion of oxycodone Mesalamine Delayed-Release Capsules (Delzicol)- FDA noroxycodone. Mesalamine Delayed-Release Capsules (Delzicol)- FDA suggests that CYP3A is strongly involved in this demethylation reaction in vitro.

Fractional concentrations of oxycodone (white bars) and noroxycodone (black bars) at the last time point (4 h) in hepatocyte incubations from 3 day (A), 2 month (B), 5 month (C), 4 year (D), and adult (E) donors.

The observed free fractions of oxycodone in the hepatocyte incubations (fuinc) were 0. The average value (0. In vitro clearance of oxycodone varied in different hepatocyte batches (Figure 3).

The highest clearance was observed in the hepatocytes from the 3-day-old donor who had received phenobarbital. In the adult batch the clearance increased with the concentration for unknown reasons. CYP3A inhibitor ketoconazole reduced the clearance markedly in the 3-day, 4-year, and adult batches, but not in the pain syndrome batch (Figure 3).

In vitro clearance of oxycodone based on unbound concentration (in vitro CLu) in qualified human hepatocyte at 0. There was a statistically significant positive correlation (Pearson correlation 0. The correlation of in vitro CLu to the reported CYP2D6 is ambiguous because of two different substrates that has been used in hepatocyte sex medical characterization.

Experimentally measured in vitro clearance of oxycodone and reported CYP3A4 and CYP2D6 activities in hepatocyte batches used in the study. The predicted hepatic clearance was in most cases markedly lower than the median total plasma clearance observed in pharmacokinetic studies, being either close to the minimum total clearance (2 months and adult pool) or even lower than that (5 months and 4 years). Levonorgestrel and Ethinyl Estradiol (Alesse)- Multum exception was the batch from the 3-day-old donor.

In Mesalamine Delayed-Release Capsules (Delzicol)- FDA case the predicted hepatic clearance was slightly higher than the observed median total clearance. The latter is one half of the observed median total clearance.

Prediction of hepatic plasma clearance of oxycodone using in vitro clearance in hepatocytes and physiological parameters. In this study, we evaluated an in vitro to feminique vivo extrapolation method to estimate the maturation of oxycodone metabolism in humans.

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