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Mouse model protocols were approved by the Institutional Animal Care and Use Committee at Colorado Fyavolv (Norethindrone Acetate and Ethinyl Estradiol Tablets)- FDA University. Whole blood was harvested throughout a time range of 0. Microsomal CYP2B protein expression was visualized by Western blot. Microsomes were prepared in loading buffer (32. Proteins were transferred to a PVDF membrane using the Trans-Blot Turbo transfer system (Bio-Rad Laboratories).

Transfer was accomplished at 1. No cross-species reactivity against Fyavolv (Norethindrone Acetate and Ethinyl Estradiol Tablets)- FDA has been reported but is anticipated considering sequence homology between the orthologs (Supplemental Table 3). Blots were developed by chemiluminesence using the Clarity Western ECL substrate (Bio-Rad Laboratories), and total protein was determined using the stain-free feature of the Bio-Rad ChemiDoc MP system.

Relative density of detected protein was calculated by dividing the pixel intensity of the chemiluminescent protein band Hydrocortisone Cream (Anusol Hc)- FDA the pixel intensity of total lane protein using Fiji software (ImageJ, Bethesda, MD) (Schindelin et al. Three independent Western blots were developed and an average relative density and standard deviation was then calculated for each microsome source.

To investigate the accuracy of microsomal metabolism of CP for each species in vivo, the observed KM and Vmax values were applied to a semiphysiologic PK model. The model consisted of three flow-limited compartments representative of whole blood, liver, and the remainder of the body (Fig.

Physiologic tissue mass and blood flow were applied for each species as described for mice, dogs, and humans (Brown et al. To capture more fully the effect of metabolism on CP PK, the model was simplistically designed.

For nonhuman species, protein binding was not included, which is physiologically representative of drug dissociation within the hepatic space for high extraction drugs (Meijer and van der Sluijs, 1989).

Fyavolv (Norethindrone Acetate and Ethinyl Estradiol Tablets)- FDA included in the model were used as the cited value in literature and were not optimized for the simulation. Simulation output was compared against clinically obtained CP PK data for each species at the appropriate dose.

Diagram of otic solution semiphysiologic model used to simulate CP pharmacokinetics in vivo.

CP delivery was modeled as intravenous bolus or infusion, depending on the study being simulated. Distribution from the plasma to the liver and remaining body was modeled based on species-specific cardiac output and fraction of that cardiac output delivered to the tissue.

The single route of elimination for CP was modeled as metabolism into 4OHCP occurring only in the liver based on the Michaelis-Menten parameters observed for each species. In vitro microsome Km and Vmax values were scaled by reported liver volume and microsomal protein per gram of liver for each species, referenced in eq. Scaling of the microsomal Vmax to represent liver Vmax in vivo was described by eq.

Equations for the rest of the body, liver, and plasma are represented glaxosmithkline ru eqs. The kinetics simulation model and semiphysiologic PK model were implemented in MATLAB version R2018a from The MathWorks, Inc.

Clinical and simulated pharmacokinetic metrics were calculated via noncompartmental analysis on Phoenix 64 WinNonlin build 8. Microsomes from humans, dogs, cats, and mice were used to determine the kinetics of 4OHCP formation (Fig. Curves were fit, and kinetic parameters were estimated under the assumption of a Fyavolv (Norethindrone Acetate and Ethinyl Estradiol Tablets)- FDA one-enzyme model (Table 3).

Curves for microsomes D1 and C2 were performed at CP concentrations dissimilar to the other microsomes because they were the first to be tested, and we had no remaining microsomes from these sources to redo the assays at the ranges shown for the rest of the microsomes. No data points were left out of any curve for the kinetics analysis (see Materials and Methods). Michaelis-Menten kinetics of 4OHCP formation in each species of microsome.

Kinetics data were collected for (A) human (H), (B) dog (D), (C) cat (C), and orlistat the mouse (M) microsomes and were fit to a one-enzyme model.

Kinetic parameters were estimated in GraphPad Prism v7. Data represent one biologic replicate for each microsome source. The assumption of the one-enzyme model was evaluated by transforming the Michaelis-Menten plots in Fig. For all Eadie-Hofstee data, we compared the fit of a line versus exponential decay and selected the best of Fyavolv (Norethindrone Acetate and Ethinyl Estradiol Tablets)- FDA two using Akaike Information Criterion corrected for small sample size implemented in GraphPad Prism 7.

Despite no evidence of atypical kinetic behavior in the Michaelis-Menten plots, linearization and subsequent fit comparisons revealed that M1, M2, and M3 kinetics behave in a biphasic fashion (Supplemental Fig. Thus, C1 kinetic behavior was regarded as monophasic in agreement with the assumptions made in the preceding. These parameters are presented in Supplemental Fig. Notably, the fast kinetic parameters for each microsome are similar to the monophasic parameters estimated from nonlinear Fyavolv (Norethindrone Acetate and Ethinyl Estradiol Tablets)- FDA. We designed a kinetic simulation model in MATLAB that simulates concentration- versus-time curves for the metabolic conversion of CP to 4OHCP, as described in the Materials and Methods.

This model was tested using each set of microsomal kinetic parameters by simulating the discontinuous kinetics assay and re-estimating the kinetics parameters to verify the accuracy of the simulation model (shown in Supplemental Fig. Supplemental Table 1 contains the comparison of empirical to simulated kinetics parameters for each microsomal source.

In all cases, the simulation model overpredicts the kinetics parameters but, on average, by no more than 2. This rome demonstrates that the observed microsomal kinetics can be adequately modeled by monophasic kinetics within reasonable error.



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