Role of Cytochrome P450 Isoforms in the Metabolism of Abamectin and Ivermectin in Rats

Abstract

Abamectin (AVM) and ivermectin (IVM) are each metabolized by rat liver microsomes to 3‘‘-O-desmethyl (3‘‘-ODMe), 24-hydroxymethyl (24-OHMe), and 26-hydroxymethyl (26-OHMe) derivatives. Microsomes from rats pretreated with dexamethasone (Dex), but not 3-methylcholanthrene (3MC), increased the formation of 3‘‘-ODMe metabolites of both AVM and IVM. Troleandomycin inhibited formation of 3‘‘-ODMe metabolites by >80% by microsomes from Dex-induced rats. Therefore, cytochrome P450 3A plays a major role in this metabolic pathway. Formation of the 26-OHMe metabolites was markedly increased by microsomes from 3MC-treated but not Dex-treated rats. Formation of 24-OHMe from AVM, but not IVM, was slightly increased by microsomes from 3MC-treated rats. Consistent with this observation, anti-rat cytochrome P450 1A1 inhibited formation of 26-OHMe metabolites of AVM and IVM by 90 and 40%, respectively. This antibody also inhibited formation of the 24-OHMe metabolite from AVM by 60% but not from IVM. Thus, cytochrome P450 1A1 is involved in the hydroxylation of the 26-methyl group of both AVM and IVM as well as the 24-methyl group of AVM but not the 24-methyl group of IVM. Keywords: Avermectin; ivermectin; metabolism; rat; cytochrome P450; isoform

Brief exposures of human body lice to sublethal amounts of ivermectin over‐transcribes detoxification genes involved in tolerance

“…Both mammals and insects form three major oxidative metabolites of IVM, 24‐ and 26‐hydroxyavermectin and 3′O‐desmethylavermectin, via phase I oxidative xenobiotic metabolism and dexamethasone (DEX) induction increases their formation (Yoon et al ., 2002). In humans, CYP3A4 metabolizes IVM (Zeng et al ., 1996) and demethylates erythromycin, a related macrocyclic lactone antibiotic (Wacher et al ., 1995). No phase II conjugates of these metabolites have been identified and most absorbed IVM is associated with bile apparently because of ATP binding cassette (ABC) transporter‐dependent efflux.…”

Influence of verapamil on the efflux and metabolism of 14C moxidectin in cultured rat hepatocytes

“…The metabolism of MOX in rats (Wu et al ., 1993), cattle (Zulalian et al ., 1994), sheep (Afzal et al ., 1994) and horses (Afzal et al ., 1997) has been described. The cytochromes P450 are the main phase I enzymes involved in the metabolism of xenobiotics, which include antiparasitic drugs: P450 3A and 1A for ivermectin in rat liver microsomes (Zeng et al ., 1996), P450 3A4 for ivermectin in human liver microsomes (Zeng et al ., 1998) and P450 3A for MOX in rat liver microsomes (Dupuy et al ., 2000).…”

“…The metabolism of MOX in rats (Wu et al, 1993), cattle , sheep and horses (Afzal et al, 1997) has been described. The cytochromes P450 are the main phase I enzymes involved in the metabolism of xenobiotics, which include antiparasitic drugs: P450 3A and 1A for ivermectin in rat liver microsomes (Zeng et al, 1996), P450 3A4 for ivermectin in human liver microsomes (Zeng et al, 1998) and P450 3A for MOX in rat liver microsomes (Dupuy et al, 2000). P-glycoprotein is a multidrug transporter which shares with P450 3A a large number of substrates and modulators, including antiparasitic drugs such as ivermectin (Schinkel et al, 1994) and MOX (Alvinerie et al, 1999a).Verapamil is a wellknown competitor substrate for the drug-binding site on the membrane transport protein Pgp (Sharom, 1997).…”

Constitutive expression of the AHR signaling pathway in a bovine mammary epithelial cell line and modulation by dioxin-like PCB and other AHR ligands

“…It is worth noting that they comprise not only widespread environmental food and feed contaminants such as DL-compounds, PAHs, and aflatoxins, but also steroid hormones and drugs widely used in the bovine practice like benzimidazole anthelmintics (Velik et al, 2004), fluoroquinolones (Fu et al, 2011), and partly avermectins (Zeng et al, 1996). If confirmed by further in vivo studies, the remarkable concentration-related increase in the expression of CYP1A1 and CYP1B1 brought about mainly by DLPCBs and B[a]P may be therefore of concern not only in view of the likely influence on drug kinetics, but also due to the potential for such CYPs to activate several xenobiotic and endogenous molecules to toxic or carcinogenic metabolites that could affect animal and human health (Williams and Phillips, 2000).…”