Predicting blood-to-plasma concentration ratios of drugs from chemical structures and volumes of distribution in humans

Hideaki Mamada,Yoshihiro Uesawa,Yukihiro Nomura,Kazuhiko Iwamoto

doi:10.1007/s11030-021-10186-7

Hideaki Mamada, Yoshihiro Uesawa + Show 2 more

Open Access

https://doi.org/10.1007/s11030-021-10186-7

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Abstract

Despite their importance in determining the dosing regimen of drugs in the clinic, only a few studies have investigated methods for predicting blood-to-plasma concentration ratios (Rb). This study established an Rb prediction model incorporating typical human pharmacokinetics (PK) parameters. Experimental Rb values were compiled for 289 compounds, offering reliable predictions by expanding the applicability domain. Notably, it is the largest list of Rb values reported so far. Subsequently, human PK parameters calculated from plasma drug concentrations, including the volume of distribution (Vd), clearance, mean residence time, and plasma protein binding rate, as well as 2702 kinds of molecular descriptors, were used to construct quantitative structure–PK relationship models for Rb. Among the evaluated PK parameters, logVd correlated best with Rb (correlation coefficient of 0.47). Thus, in addition to molecular descriptors selected by XGBoost, logVd was employed to construct the prediction models. Among the analyzed algorithms, artificial neural networks gave the best results. Following optimization using six molecular descriptors and logVd, the model exhibited a correlation coefficient of 0.64 and a root-mean-square error of 0.205, which were superior to those previously reported for other Rb prediction methods. Since Vd values and chemical structures are known for most medications, the Rb prediction model described herein is expected to be valuable in clinical settings.Graphical abstract

Highlights

Blood-to-plasma ratio (Rb) is defined as Cb / Cp. It is an important clinical parameter for calculating pharmacokinetic (PK) parameters based on blood concentrations from those based on plasma concentrations
Rb is an important variable for the calculation of PK parameters based on blood concentrations from those based on plasma concentrations
The present study found that volume of distribution (Vd) is an important parameter for constructing Rb prediction models

Summary

Introduction

Blood-to-plasma ratio (Rb) is defined as Cb (blood concentration of compound) / Cp (plasma concentration of compound). In the case of butorphanol, which shows Rb value of approximately 2 to be concentrated in blood cells, butorphanol exposure calculated from plasma is half the exposure calculated from blood [2]. For precise PK calculations, these parameters must be converted to blood-derived values by Rb. Regrettably, the number of drugs for which experimental Rb values have been reported is limited; clinicians must often make a rough approximation, e.g., by assuming that Rb = 1 [3, 4]. The number of drugs for which experimental Rb values have been reported is limited; clinicians must often make a rough approximation, e.g., by assuming that Rb = 1 [3, 4] This assumption’s rationale is not clear, and the analyses using this value can be inaccurate

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