Metabolism of Cycloprothrin in Rats

Abstract

Absorption, distribution, excretion and metabolism of ¹⁴C-cycloprothrin [(RS)-α-cyano-3-phenoxybenzyl (RS)-2, 2-dichloro-1-(4-ethoxyphenyl)-[3-¹⁴C]cyclopropanecarboxylate] were studied in rats after single (50mg/kg) or consecutive (50mg/kg, once a day for one week) oral administration. After single oral administration, the radiocarbon was rapidly and almost completely excreted into the feces and urine (63 and 36%, respectively) within 168hr. Radiocarbon levels in the tissues reached maximum 3hr after single oral administration and then decreased with time. Concentrations of radioactivity in the tissues after repeated administration were about 3.6 times higher than those after single administration. The radioactivity peaked within 3 days after initial administration in the tissues except the fat, skin and cecum, and decreased with time after final administration. Radioactivity levels were relatively high in the fat and skin. Disappearance of the radioactivity from the fat and skin was slower than from the other tissues. Residue levels of radiocarbon in each tissue on the 7th day after final administration was less than 50ng of the parent compound equivalents/g tissue. Cycloprothrin was readily metabolized by cleavage at the ester linkage and oxidation of the ethoxy position of the acid moiety. (RS)-α-cyano-3-phenoxybenzyl (RS)-2, 2-dichloro-1-(4-hydroxyphenyl)cyclopropanecarboxylate (HO-cycloprothrin), (RS)-2, 2-dichloro-1-(4-ethoxyphenyl) cyclopropanecarboxylic acid (C₂H₅O-acid), (RS)-2, 2-dichloro1-(4-hydroxyphenyl)cyclopropanecarboxylic acid (HO-acid) and (RS)-2, 2-dichloro-1-[4-(2-hydroxyethoxy)phenyl]cyclopropanecarboxylic acid (HO-C₂H₄O-acid) were found in the feces and urine. As much as 48% of the administered radiocarbon excreted as the parent compound in the feces. HO-Acid was a predominant metabolite in both the urine and feces, it amounting to 39% (31% in the urine and 8% in the feces, respectively) of the dose.