Exploring the Relationship of Drug-Induced Neutrophil Immaturity & Haematological Toxicity to Drug Chemistry Using Quantitative Structure – Activity Models

J.   M.   Delieu; R.   W.   Horobin; J.   K.   Duguid

Abstract

An investigation of the relationships between physicochemical features of ten antipsychotic drugs and previously reported influence of these drugs on neutrophil maturity was made. A quantitative structure-activity relations (QSAR) approach was adopted, in which several numerical parameters describing physicochemical characteristics of the antipsychotics were estimated. Possible connections between these parameters and neutrophil maturity were explored. Influence of drug physicochemistry on the incidence of agranulocytosis and neutropenia reported in the literature was documented. Overall it was found that drugs with the greatest tendency to induce neutrophil immaturity (chlorpromazine, clozapine and olanzapine) also showed the greatest tendency to cause agranulocytosis and neutropenia. Moreover marked induction of neutrophil immaturity occurred with compounds of moderately amphipathic character, whose amphipathic indices (AI) fell in the range 3 – 5; higher or lower AI values correlated with less immaturity. Consideration of the QSAR findings suggest that toxicity could be associated with selective uptake into the most fluid intracellular membranes, those of the endoplasmic reticulum and the outer mitochondrial membrane. The AI hazard zone (AI = 3 – 5) does constitute a predictive tool to assess risk of agranulocytosis and neutropenia arising from antipsychotic and other psychoactive drugs — and not only risk arising from medication but also from experimental or even proposed compounds.

Keywords: Agranulocytosis, antipsychotics, neutropenia, QSAR, chlorpromazine, clozapine, olanzapine, risk prediction