Tricaine methanesulfonate, administered at a dose of 150 mg/kg i.p., produced a flaccid
paralysis and loss of the righting reflex in a number of poikilothermic species including the frog. Leopard frogs (Rana pipiens) given 150 mg/kg i.p. regained the righting reflex at 113 +/- 28 (S.D.) minutes after injection. A similar dose administered i.p. to mice produced no apparent pharmacological response. The
biological half-life (T1/2) of
tricaine in frogs (R. pipiens) was about 70 minutes at temperatures of 23 and 37.5 degrees C; at 7 degrees C the T1/2 was 309 minutes. In contrast, in the mouse the
drug was metabolized so rapidly that 5 minutes after i.p. administration of 5 mg of
tricaine methanesulfonate (250 mg/kg) none of the unchanged
drug could be recovered from the animal. It was, however, recovered quantitatively as Bratton-Marshall reacting metabolites, including
m-aminobenzoic acid. Incubations of
tricaine with serum from bullfrogs, mice and humans indicated that the
drug was metabolized to
m-aminobenzoic acid with an apparent Km of 3 X 10(-3) M for the reaction. The Vmax for incubations of the
drug with bullfrog and human serum was 40 nmol/min/ml of serum, whereas in mouse serum it was 93 nmol/min/ml of serum. In vitro studies with liver homogenates showed that mouse liver metabolized
tricaine 39 times more rapidly than frog liver. We conclude, therefore, that the liver is the major site of
tricaine hydrolysis in mammals and that the selective toxicity of
tricaine for poikilotherms is a consequence of their slower rate of hepatic biotransformation of
tricaine.