The effect of solvents on drug metabolism in vitro

Nine water-miscible organic solvents, methanol, ethanol, acetone, ethoxyethanol, tetrahydrofuran, dioxane, dimethylformamide, acetonitrile, and dimethyl sulfoxide were each used with five commonly employed substrates of in vitro microsomal mixed-function oxidase assays containing liver 9,000g supernatant fractions from rats treated with phenobarbital or Aroclor 1254. When the metabolism of aminopyrine, aniline, 7-ethoxycoumarin, p-nitroanisole, and benzo[a]pyrene was determined in the presence of these solvents, varying degrees of stimulation and inhibition were observed. These effects were dependent on the substrate studied, the particular solvent incorporated into the assay, and the rat liver 9000g supernatant fraction used. These differential effects were also observed when 2-aminoanthracene was metabolically activated in the Ames Salmonella/mammalian-microsome mutagenicity test, but were not as dramatic when benzo[a]pyrene was tested.