The neonicotinoids, one of the new classes of insecticides, are very potent for protecting crops against piercing-sucking insects (Tomizawa & Casida, 2003). Some of them are also used in veterinary medicine, especially for controlling fleas in cats and dogs (Mencke & Jeschke, 2002; Schenker et al., 2003). These insecticides include imidacloprid, nitenpyram, acetamiprid, thiacloprid, thiamethoxam, clothianidin, and dinotefuran. Based on the differences in chemical structure, these neonicotinoids are divided into three subclasses: ‘chloronicotinyl’ (the first-generation neonicotinoids, e.g., imidacloprid, nitenpyram, acetamiprid, and thiacloprid), ‘thianicotinyl’ (the second-generation neonicotinoids, e.g., thiamethoxam and clothianidin) and ‘furanicotinyl’ (the third-generation neonicotinoids, e.g., dinotefuran) (Maienfisch et al., 2001; Wakita et al., 2003). The classification, first, second or third generation coming from differences in their chemical structures, has no relation with their selectivity of binding of insect/vertebrate nAChR or therapeutic advantages. In this review, we focus on three neonicotinoids that are used in veterinary medicine, including imidacloprid, nitenpyram, and dinotefuran (Fig. 3).
Therapeutic use of neonicotinoids. Imidacloprid: Imidacloprid [Advantage® (9.1% imidacloprid w/w); Bayer Animal Health, Shawnee, KS, USA] a first-generation neonicotinoid insecticide, was first marketed by Bayer Animal Health as Advantage® in 1996. It has strong insecticidal activity against sucking insects. Imidacloprid is used topically (7.5–10 mg/kg b.w.) once a month as a spot-on product in dogs and cats that are ≥4 weeks old (Arther et al., 1997). However, the approved dose range is wider (8.8–20 mg/kg). It rapidly kills adult fleas on dogs and cats and breaks the flea life cycle before eggs being laid (Arther et al., 1997; Jacobs et al., 1997). About 96% of adult fleas are killed within 8 h of imidacloprid application and the fleacidal effect is persistent for 34 days, as it is stored in the sebaceous glands of the animals and is not washed out by shampooing (Arther et al., 1997).
Imidacloprid is also available as a mixture with permethrin [K9 Advantix® (8.8% imidacloprid + 44.0% permethrin w/w); Bayer Animal Health] to kill and repel ticks in dogs (Epe et al., 2003) and with moxidectin [Advantage Multi® (10% imidacloprid + 1% moxidectin for cats (2.5% for dogs) w/w; Bayer Animal Health] to prevent heartworm disease and to treat and control gastrointestinal (GI) nematodes and mites in dogs and cats (Arther et al., 2003, 2005).
Pharmacokinetics of imidacloprid: By topical application, imidacloprid spreads over the skin surface and throughout the hair coat of dogs and cats within 12 h (Fichtel, 1998; Mehlhorn et al., 1999). Imidacloprid is localized in the water-resistant lipid layer of the skin surface (Mehlhorn et al., 1999) and is released slowly over a period of time. This characteristic can account for its prolonged insecticidal action of ∼1 month. As this insecticide is applied topically, but not systemically absorbed, in dogs and cats, the pharmacokinetics in these species is not well understood.
The pharmacokinetics of systemic imidacloprid has been studied in rats. When administered orally to rats, 92–99% of imidacloprid is absorbed from the GI tract and is widely distributed throughout the body [California Environmental Protection Agency (CEPA) (2006) Imidacloprid-Risk Characterization Document: Dietary and drinking water exposure. Available at: http://www.cdpr.ca.gov/docs/risk/rcd/imidacloprid.pdf. FDA-Federal Register (2000) Imidacloprid (Admire, Provado, Gaucho) – Pesticide Petition Filing, 65, 7010]. The drug reaches the maximum plasma concentration (Cmax) at 1.1 and 2.5 h after the administration of 1 and 20 mg/kg b.w., respectively. The distribution volume (Vd) is ∼84% of the total body volume and the distribution half-life (t½) is ∼3 h for both i.v. and oral administrations.
There are two major pathways for the metabolism of imidacloprid in rats. First, imidacloprid is cleaved into desnitro-imidacloprid and 6-chloronicotinic acid. The desnitro-imidacloprid is eliminated in the urine. The 6-chloronicotinic acid is conjugated with glutathione to form mercapturic acid and then mercaptonicotinic acid. The mercaptonicotinic acid ultimately conjugates with glycine to form hippuric acid for excretion. In the second pathway, there is hydroxylation in the imidazolidine ring which is followed by the formation of olefinic imidacloprid (the unsaturated metabolite). The metabolism pathways are similar among hens, goats, and rats. Within 24–48 h of administration, the metabolites are excreted mainly in the urine and a small amount in the feces. These findings suggest that the systemically absorbed imidacloprid is eliminated rapidly from the body, which contributes to its safety in animals.
Nitenpyram: Nitenpyram [Capstar® (11.4 or 57 mg of nitenpyram); Novartis Animal Health, Greensboro, NC, USA] another-first generation neonicotinoid, was first marketed in 1995 by Takeda Chemical Industries, Ltd. It provides rapid flea relief in dogs and cats and has the highest initial overall percent kill when compared with fipronil, a blocker of GABA-gated Cl− channels, imidacloprid, selamectin, a macrocyclic lactone, and cythioate, an organophosphate (Schenker et al., 2003). Nitenpyram is ≥99% effective against fleas on cats and dogs within 3 h of administration, and 100% effective against fleas in both cats and dogs within 8 h of administration (Schenker et al., 2003).
Nitenpyram is administered orally (1 mg/kg b.w.) for the short-term control of fleas in dogs and cats. Fleas begin to fall from the animals 30 min postadministration (Dobson et al., 2000) and one dose can protect animals for 1–2 days (Rust et al., 2003).
The fast fleacidal action of nitenpyram is particularly important for animals suffering from flea-bite allergic dermatitis and for the fast control of adult fleas in an integrated flea control strategy (Schenker et al., 2003). However, this drug alone cannot protect animals for more than 48 h after administration. It is normally used in combination with lufenuron [Program® (lufenuron); Novartis], an insect development inhibitor, to provide continuous flea control.
Pharmacokinetics of nitenpyram: As nitenpyram is highly lipophilic, it should be administered orally after the meal in order to increase bile flow to help dissolve the chemical, thereby increasing GI absorption of the drug. It is rapidly absorbed from the GI tract with the time to reach maximum concentration (Tmax) of 1.21 h in dogs and 0.63 h in cats and the Cmax of 4.8 μg/mL in dogs and 4.3 μg/mL in cats (Schenker et al., 2001). The plasma t½ of nitenpyram in dogs and cats are 2.8 and 7.7 h, respectively (Schenker et al., 2001). Nitenpyram undergoes hydroxylation, which is followed by conjugation in the liver. The conjugates of nitenpyram are excreted in the urine and nitenpyram is not accumulated in body tissues. The metabolites of nitenpyram are completely excreted in urine within 48 h of oral administration to dogs and cats (Schenker et al., 2001).
Dinotefuran: Dinotefuran [Vectra 3D® (4.95% dinotefuran + 0.44% pyriproxyfen + 36.08% permethrin w/w); Summit VetPharm, Fort Lee, NJ, USA] is a third-generation neonicotinoid, which was first marketed in 2002 by Mitsui Chemicals Group. It has a characteristic (±)-tetrahydro-3-furylmethyl moiety instead of the pyridine-like moiety of other neonicotinoids (Wakita et al., 2003).
Dinotefuran is used as a topical spot-on product (7–16 mg/kg b.w.) and has a slightly faster knockdown action than imidacloprid (killing 96% fleas in 6 h and 100% within 12 h) [Bowmann, D.D. & Ball, C.A. (2007) Introducing a brand new flea technology. Summit VetPharm, 1(4). Available at: http://www.summitvetpharm.com]. The retaining residual activity can prevent flea larvae for 44 days and control adult fleas up to 16 days (spray formulation) or 23 days (spot-on formulation) (Correia et al., 2008). It is available as a mixture with permethrin (to kill ticks) for use in dogs and pyriproxifen, an insect growth regulator (to kill larvae), for use in cats. The combinations of these compounds effectively break the life cycle of the fleas, including larvae and adults, thereby preventing re-infestations.
Pharmacokinetics of dinotefuran: The pharmacokinetics of dinotefuran has been studied in rats, but not in dogs or cats. After oral administration, the absorption is >90% regardless of the dose and the drug is distributed throughout the body [EPA (2004) Dinotefuran: Pesticide Fact Sheet 2004. Available at: http://www.epa.gov/opprd001/factsheets/dunotefuran.pdf]. The Cmax in milk and fetal tissues is identified as 0.5 h after oral administration. The plasma t½ is 3.6 h at the low dose and 15.2 h at high dose. Most of the dinotefuran is excreted as the parent compound into urine and only a small amount is excreted into feces within 24 h of oral administration (Ford & Casida, 2006). Less than 10% of dinotefuran can be metabolized into numerous minor metabolites by N-demethylation, nitro reduction, tetrahydrofuran hydroxylation, and N-methylene hydroxylation and amine cleavage (Ford & Casida, 2006).