Analysis of Complexation Interactions between Metal Ions and Drugs under Pseudo-physiological pH Conditions by a High-throughput Screening Method Using a Solid-phase Extraction Cartridge

Abstract

A high-throughput screening method for the complexation between metal ions and drugs was established by combining solid-phase extraction (SPE) using a nitrilotriacetic acid (NTA) modified silica spin cartridge with subsequent HPLC analysis. First, a test metal ion solution was passed through the NTA cartridge, then a test drug solution diluted in phosphate buffered saline (pH 7.4) was passed through the metal-chelated NTA cartridge. The complexation behavior between the metal and the drug on the NTA cartridge was evaluated by HPLC quantification of the drug in the SPE eluate. Comprehensive analysis of the complexation behavior between 11 different metal ions and 55 drugs showed that Cu²⁺, Ni²⁺, Co²⁺, Zn²⁺, Cr³⁺ and Fe³⁺ formed complexes with 12, 5, 4, 2, 1 and 1 kinds of drugs, respectively. Bromazepam selectively formed complexes with Cu²⁺, Ni²⁺ and Co²⁺.