Takahide Uchimura

The objective of this study was to predictR_b(blood/plasma ratio) in humans using a simple method. Human and ratR_band free fraction in plasma (f_p) values were obtained from the literature. The ratio of total red blood cell concentration to the free concentration in plasma (K_b) was calculated usingf_pandR_b. Four methods were used for the prediction ofR_b: (A) use of ratR_b; (B) use ofR_bcalculated from ratK_band humanf_p; (C) correlation of human log ((1−f_p)/f_p) and human logK_b; and (D) correlation of logDwith human logK_b. TheR_bof 96 compounds in humans ranged from 0.52 to 2.00, with an average of 0.89. A significant correlation was observed among human logK_b, human log ((1−f_p)/f_p), and logD; however, no obvious correlation was observed among humanR_b, human log ((1−f_p)/f_p), and logD. The errors within 1.25‐fold for methods A–D were 68.3%, 77.6%, 61.5% and 64.8%, respectively. All predictive methods considered here were superior to the use of the average value of humanR_borR_b=1. RatR_bcorrected by humanf_pimproved the accuracy of the prediction. Method B was the most accurate of the four methods. Copyright © 2010 John Wiley & Sons, Ltd.

The purpose of this study was to develop a method for estimating the hepatic clearance (CL_h) without using a protein binding test. This method allows the simultaneous evaluation of the intrinsic hepatic clearance (CL_int) with a correction for microsomal binding, and the free fraction in the serum (fu). It uses the decrease in metabolic velocity achieved by decreasing the free fraction of a compound in the incubation mixture (fu_inc) by the addition of serum, and by changing the microsomal protein concentration. This method is denoted as the ‘matrix inhibition method’, because it uses the inhibition of the metabolic velocity by the incubation matrix. The metabolic rates of eight compounds (diazepam, imipramine, warfarin, and compounds A–E) were evaluated under several incubation conditions using rat serum and microsomes. The correlation ofCL_intevaluated using the method and using equilibrium dialysis after theCL_intwas corrected for microsomal binding wasr = 0.968. The correlation offu · CL_intwasr = 0.996. Although the method required a high enoughfuandfu_microsomesdifference among the reaction conditions for each compound, it could evaluateCL_intandfusimultaneously and easily by adding additional reaction conditions to the metabolic stability tests performed in ADME screening. Copyright © 2007 John Wiley & Sons, Ltd.