EFFECT OF ,-DIFLUORO SUBSTITUTION ON THE DISPOSITION AND PHARMACOLOGICAL EFFECTS OF 4-CHLOROAMPHETAMINE IN RATS

¹ The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana

,-Difluoro-4-chloroamphetamine has a pK of 6.8 compared to 9.3 for 4-chloroamphetamine. At physiological pH, the difluoro compound thus exists primarily as a neutral molecule, whereas the parent drug exists as a cation. The tissue distribution of the two drugs when they were injected into rats was different. Whereas the relative concentration of 4-chloroamphetamine in tissues was kidney > lung > brain > spleen > liver > heart > epididymal fat, the difluoro compound localized chiefly in epididymal fat and was present in all other tissues in concentrations lower than those of 4-chloroamphetamine. The distribution of 4-chloroamphetamine between particulate and soluble fractions of brain was altered only slightly by the difluoro substitution. The difluoro compound disappeared from whole body of rats with shorter half-life (1.3 hours) than that of 4-chloroamphetamine (7.5 hours). The difluoro compound was excreted unchanged into the urine to a much smaller degree than was 4-chloroamphetamine. These results suggest the difluoro compound is metabolized more rapidly and to a greater extent in rats than is 4-chloroamphetamine. Higher doses of the difluoro compound were required to produce drug levels in brain equal to those of 4-chloroamphetamine and the levels of the difluoro compound fell more rapidly. There was less hyperthermia and central nervous system stimulation caused by the difluoro compound even on the basis of comparable drug levels in brain. ,-Difluoro-4-chloroamphetamine reduced 5-hydroxytryptamine and 5-hydroxyindoleacetic acid levels in brain as did 4-chloroamphetamine, but because of the altered tissue distribution and more rapid disappearance of the difluoro compound, its effect on brain 5-hydroxyindoles was transient and occurred only at higher doses than with 4-chloroamphetamine. Thus, substitution of two fluorines on the carbon of 4-chloroamphetamine, probably because of the lowered pK, markedly altered the physiologic disposition and, hence, the pharmacologic effects of the drug.