Identification of cytochrome P4503A as the major enzyme sub-family responsible for the metabolism of 22,23-dihydro-13-O-[(2-methoxyethoxy)methyl]avermectin B₁aglycone by rat liver microsomes

Abstract

1. Metabolism of 22,23-dihydro-13-O-[(2-methoxyethoxy)methyl]-avermectin B1 aglycone (MEM-H2B1), a new avermectin, by rat liver microsomes has been studied. Metabolites identified were formed by demethylation of the methoxyethoxymethoxy (MEM) side chain, loss of the MEM side chain, partial cleavage and further oxidation of the MEM side chain, and oxidation of the aglycone after cleavage of the MEM side chain. 2. The specific cytochrome P450 isoforms involved in the metabolism of MEM-H2B1 were identified through immunoinhibition studies. Among several antibodies prepared against various cytochrome P450s, only anti-rat P4503A IgG inhibited MEM-H2B1 metabolism by liver microsomes from the untreated rat. Moreover, troleandomycin, a selective suicide inhibitor for enzymes of the cytochrome P4503A family, inhibited the total metabolism by > 80%. These results clearly indicate that cytochrome P4503A is primarily responsible for the metabolism of MEM-H2B1. 3. Secondary metabolism was evident in the metabolism of MEM-H2B1 by dexamethasone and phenobarbital induced liver microsomes, where different isoform(s) of cytochrome P4503A could be involved in these multiple step reactions.

Clinical pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoes

“…Yet, assays with radiolabeled ivermectin imply that M1 and M2 are the major in vitro metabolites of ivermectin [41]. Interestingly, M1 was also produced by rat, pig, sheep and dog microsomes, which suggests that the O-demethylation of ivermectin may be also relevant for the treatment of livestock and domestic animals [50][51][52][53]. Drugdrug interaction studies were carried out in animals to assess the effect of CYP inhibition and induction on the pharmacokinetics of ivermectin.…”