Caffeine distribution in acute toxic response among inbred mice

The median lethal dose (LD50) and the median lethal concentration (LC50) of caffeine administered intravenously (i.v.) and orally (p.o.) were calculated in adult male CD2F1/Crl BR mice. Acute toxic behavioral responses to the drug were observed after administration via the two routes. Deaths followed severe tetanic convulsions: some animals had transient convulsions and survived, and others presented no acute toxicity. In a further study, the LD50 of caffeine was given i.v. and by gavage to animals randomly paired. At the death of one of the two mice the other was killed and caffeine assayed in blood and tissues of both. Different patterns of distribution were observed inter- and intra-route of administration, animals which died always having higher drug levels, although they had received the same dose. These findings suggest that besides the well-known factors affecting acute toxic response to exogenous compounds, drug distribution also has to be taken into account in a multifactorial toxicological investigation.