sensitive uptake (Δuptake) of 12 cationic compounds (celiprolol, acebutolol, pindolol, bisoprolol, metoprolol, propranolol, procainamide, quinidine, flecainide, clonidine, pyrilamine, and verapamil)

No abstract

We previously reported that there is 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 the 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). The log likelihood difference (LLD) between the covariance and noncovariance model analysis was weakly altered by the change of the inter-individual difference of volume of distribution (V) and systemic clearance (CL), and was slightly altered by the change of intra-individual error of blood concentration measurement. The LLD was also weakly altered by the change of the blood sampling design and by the number of subjects in clinical trials. In contrast, the LLD was significantly affected by the change of the range of F. However, the LLD value for the clinical trial of the drug with 80-100％ of F was still statistically significant. Therefore, we should use the covariance model for the population pharmacokinetic analysis for drugs with mean F below 80％.