Influence of alkaline pH on the direct lethal action of miconazole against Candida albicans

The imidazole group of miconazole is subject to protonation (pKa approximately 6.5). Earlier we suggested that the direct lethal action (DLA) of miconazole against Candida albicans requires nonprotonated drug molecules. DLA declined in intensity as pH was decreased from 6.0. At pH > 6.5 most molecules of miconazole exist in the nonprotonated state, but drug also becomes less soluble. Viability studies were designed to assess DLA in relation to alkaline pH. DLA was clearly inhibited with increasing as well as decreasing pH (i.e., pH < 6.0 and > 7.0), suggesting that nonprotonated neutral drug molecules must be in solution or in extremely small aggregates to elicit DLA, and that the nonprotonated species itself is more soluble at pH 6.0-7.0 than under more alkaline conditions.