Chlorobutanol, a Pharmaceutical Preservative and Sedative Hypnotic, Inhibits Brain Type Voltage Gated Sodium Channels

Abstract

Introduction- Chlorobutanol (1,1,1-trichloro-2-methyl-2-propanol) is a widely used chemical preservative for injectable drugs, eye drops, mouth washes, and cosmetics. It is an analgesic, experimental general anesthetic, and sedative hypnotic in man. The mechanism of action of chlorobutanol is unclear. Our goal was to test whether chlorobutanol inhibits brain type voltage gated sodium channels. Methods- Mammalian Nav 1.2 voltage gated sodium channels were expressed in Xenopus oocytes by injecting the alpha subunit cRNA. Inward sodium currents were measured with two-electrode voltage clamp using standard depolarization protocols. The study was approved by our institutional animal care and use committee. Results- Chlorobutanol was tested at concentrations ranging from 0.03 to 10 mM. Chlorobutanol reversibly inhibited closed, resting channels and inactivated channels in a concentration dependent manner. The voltage dependence of activation was shifted in the depolarizing direction. Fast inactivation voltage dependence was not affected. There was little state dependent block and no apparent use dependence. Discussion and Conclusions- Chlorobutanol inhibited Nav 1.2 channels at concentrations less than those used to preserve pharmaceuticals. Its use as a preservative in injectable methadone and local anesthetic solutions, and in eye drops likely adds an analgesic component to these solutions.