Dimenhydrinate (Dramamine) is the 8-chlorotheophylline salt of diphenhydramine. Dramamine is commercially available as a solution containing 50 mg dimenhydrinate per ml in 50% propylene glycol/5% benzyl alcohol. Studies in which New Zealand albino female rabbits received dimenhydrinate, i.v. and/or im, revealed evidence of inhibition of drug clearance apparently due to exposure to vehicle. Following im administration of 8-chlorotheophylline to naive rabbits, peak drug levels of 420 ng/ml were attained in 60 min which declined exponentially to near baseline levels within 7 hr. Animals treated with an additional im dose 2 days later achieved blood drug levels of > 2000 ng/ml which were sustained for the duration of the experimental period. Initial i.v. administration of 8-chlorotheophylline resulted in peak concentration of about 5000 ng/ml which declined to near baseline levels within 90 min, while 8-chlorotheophylline (i.v.) blood levels in rabbits exposed to im vehicle (2 days prior) appeared to plateau around 250 ng/ml after 60 min. Acute, short-term exposure to im vehicle did not appear to elicit the altered elimination profiles. An investigation of the influence of the recommended vehicle on the bioavailability and clearance of dimenhydrinate in isolated rabbit liver microsomes revealed that vehicle at concentrations > 0.68 mg/ml significantly decreased the percent of drug metabolized. This effect was directly proportional to the concentration of vehicle added. Studies showed this effect to be due to the propylene glycol component of the vehicle.