We previously reported that there is a positive correlation between the oral clearance (CL/F) and the apparent volume of distribution (V/F) of the drugs with variable bioavailability (F). The aim of the present study using the computer simulation method was to evaluate the usefulness of the population pharmacokinetic analysis model assuming the covariance of CL/F and V/F (ωCL/F,V/F). The total clearance (CL), volume of distribution (V), and F values in the 1-compertment model were generated for 50 hypothetical subjects, and the peak and/or trough blood concentrations were calculated at steady state following repetitive bolus dosing. The population parameters could be estimated precisely by the covariance model. In addition, the precision of Bayesian analysis using the covariance model was high as compared with that using the non-covariance model. Furthermore, the relative F values estimated from individual CL/F and V/ F values (adjusted as mean value = 1) were well correlated with the true F values. These findings suggest that the covariance model assuming ωCL/F,V/F is useful for the population pharmacokinetic analysis of the drugs with variable bioavailability.
We recently found the H + /quinidine (QND) antiport system in canine kidney MDCK and porcine kidney LLC-PK1 cells. The aims of the present study were to confirm the presence of the H + /QND antiport system in human embryonic kidney (HEK) 293 cells, and to investigate the substrate specificity of the system. The cellular uptake of 100 µM QND into HEK293 cells was decreased by acidification of extracellular pH and by NH4Cl-induced alkalization of intracellular pH. In addition, a lipophilic cationic drug, diphenhydramine (DPH), significantly decreased the QND uptake in HEK293 cells. In order to evaluate the substrate specificity of the renal H + /QND antiport system, we investigated the DPH-sensitive uptake (Δuptake) of 12 cationic compounds (celiprolol, acebutolol, procainamide, pindolol, bisoprolol, metoprolol, flecainide, clonidine, pyrilamine, QND, propranolol, and verapamil). The Δuptake positively correlated with their lipophilicity (Log D) values, and negatively correlated with their polar surface area (Log PSA) values. In contrast, the Δuptake did not correlate with their molar volume (MV), molar refractivity (MR), or polarization (PO). These findings indicate that an H + /QND antiport system is present in HEK293 cells, and that the Log D and Log PSA of drugs are important factors responsible for the transport activity of the postulated H + /lipophilic cation antiporter in the kidney.
We previously reported a positive correlation between the oral clearance (CL/F) and the apparent volume of distribution (V/F) of drugs with variable bioavailability (F). The aim of the present study using a computer simulation method was to further evaluate the usefulness of the population pharmacokinetic analysis model assuming the covariance of CL/F and V/F (ωCL/F, V/F). We assumed variable bioavailability (F) not only in intestinal absorption, but also in hepatic first-pass extraction and transdermal absorption. The log likelihood difference (LLD) between the covariance and conventional (non-covariance) model analysis was very similar to the LLD between the true and conventional model analysis. The individual relative F (Frel) values estimated with the covariance model analysis was also similar to the Frel values estimated with the true model analysis. Therefore, we should use the covariance model and/or the true model positively for population pharmacokinetic analysis for drugs with variable F.
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