Pharmacokinetics and Metabolism of Toltrazuil and Its Major Metabolites after Oral Administration in Broilers

Abstract

Toltrazuril is a symmetrical tiazinetrione compound. It is active against all intracellular developmental stages including those of schizogony and gametogony. In this study the disposition kinetics of toltrazuril (TZR) and its major metabolites (TZR-SO and TZR-SO 2 ) in broiler chickens after single oral administrations of 10 or 20 mg/kg were investigated. Mean plasma concentrations of TZR peaked at 16.4 and 25.2 μg/mL at 5.0 and 4.7 h after dosing, respectively. TZR was converted to the short-lived intermediary metabolite toltrazuril sulfoxide (TZR-SO), and then further metabolized to the reactive toltrazuril sulfone (TZR-SO 2 ) being actually more slow eliminated with 80.3 and 82. 9 h than TZR (10. 6 and 10. 7 h) or TZR-SO (14. 8 and 15. 3 h) in low and high dosing groups, respectively. Prolonged elimination half-life of TZR-SO 2 could be interpreted as the persistent clinical efficacy of TZR in the treatment of protozoal parasites infection.Key words: broiler, pharmacokinetics, toltrazuril, toltrazuril sulfone, toltrazuril sulfoxide J. Poult. Sci., 50: 257-261, 2013 Introduction Coccidiosis is a particularly dangerous disease in the poultry industry where chickens are maintained on the floor (Greif, 2000). Anticoccidial drugs of many different chemical types have been the dominant means to prevent and control the coccidiosis (Polozowski, 1993;Greif et al., 2001). However, the massive and uncontrolled use of anticoccidial drugs has resulted in the emergence of drug-resistant parasites (Suo X et al., 2006)., 5-triazinane-2, 4, 6-trione, is a symmetrical triazinetrione compound. It has coccidiocidal action against all intracellular developmental stages including those of schizogony and gametogony (Mehlhorn et al., 1984;Haberkorn and Stoltefuss, 1987). It has been reported to be effective against all coccidial species in most animal species, such as chickens (Mehlhorn et al., 1984), ducks (Chauve et al., 1994), dogs (Daugschies et al., 2000), mice (Haberkorn et al., 1983), pigeons (Van Reeth and Vercruysse, 1993), piglets (Mundt et al., 2007) and rabbits (Peeters and Geeroms, 1986).TZR undergoes extensive metabolism to toltrazuril sulfoxide (TZR-SO) and then to TZR-SO 2 , which appears to have anticoccidial activity (Benoit et al., 1993;Lang et al., 1996;Bach et al., 2003;Mundt et al., 2007) (Fig. 1). Generally, triazines produced the same types of metabolites in most species, but the ratios of the metabolites showed the species differences (Furr and Kennedy, 2000;MacKay, 2006;Kim et al., 2010;Lim et al., 2010). Also, TZR is almost exclusively metabolized to TZR-SO 2 , also known as ponazuril (PZR), which has been recognized as the marker metabolite in a number of tissues. Although TZR is commonly used for the prevention and treatment of coccidosis in broilers, the pharmacokinetic and metabolic profiles of TZR in broilers have received minimal investigation. There must be assessed not only in terms of good clinical efficacy but also considering the pharmacokinetics and metabolism of TZR in broilers for the rat...

Pharmacokinetics of toltrazuril and its metabolites toltrazuril sulphoxide and toltrazuril sulphone in pregnant and non-pregnant goats

“…Furthermore, our results showed that the T 1/2λz of TZR in non-pregnant goats was 64.07 h. This T 1/2λz was nearly similar to that recorded in pigs (68.9 h, 20 mg/kg TZR, Lim et al 2010). Lower values of T 1/2λz were observed following oral administration of TZR in rabbits and broilers (56.70 and 10.70 h, respectively) compared to those reported in our study (Kim et al 2010(Kim et al , 2013. In contrast, the T 1/2λz found in calves and sheep (154.00 and 160.00 h, respectively;EMEA 2000;Al-Qadri et al 2020) were higher than that reported in our study for non-pregnant goats, advocating that TZR is more rapidly eliminated in goats compared to sheep and calves.…”

“…This value was comparable to that reported for ewes and rabbits that received the same dose orally (20 mg/kg) (38.00 and 39.4 µg/ml, respectively) (Kim et al 2010;Al-Qadri et al 2020). On the contrary, it was higher than that found in piglets, pigs, and broiler chickens administered TZR at 20 mg/kg (7.50, 8.18, and 25.20 µg/ml, respectively) (EMEA 1999;Lim et al 2010;Kim et al 2013), calves that received TZR orally at 15 mg/kg (33.41 µg/ml) (EMEA 2000), and horses that were given TZR orally at 10 mg/kg (4.5 µg/ml) (Tobin et al 1997). Furthermore, our results showed that the T 1/2λz of TZR in non-pregnant goats was 64.07 h. This T 1/2λz was nearly similar to that recorded in pigs (68.9 h, 20 mg/kg TZR, Lim et al 2010).…”

“…The pharmacokinetics of TZR have been described in multiple species including rabbits (Hu et al 2010;Kim et al 2010), broilers (Kim et al 2013), calves (EMEA 2000), pigs (Lim et al 2010), ewes (Al-Qadri et al 2020), and horses (Tobin et al 1997). In these animals, TZR was well absorbed following oral administration and showed long plasma half-lives.…”

Pharmacokinetics and tissue residue of toltrazuril in broiler chickens

“…However, different results were obtained in broiler chickens at dose of 10 mg/kg (16.4 μg/ml attained at 5.0 h) and at dose of 20 mg/kg (25.2 μg/ml attained at 4.7 h) [12], in rabbits at dose of 10 mg/kg (30.2 μg/ml attained at 20.0 h) [10], in rats (25.0 μg/ml, 20 mg/kg, [13] and in calves at dose of 15 mg/kg (33.41μg/ml) [13] Similar findings were obtained in piglets at dose of 20 mg/kg (7.5 μg/ml) [14], in horses at dose of 10 mg/kg (4.5 μg/ml) [15]. The apparent elimination half-life of toltrazuril was 14.92 and 16.14 h after the first and second dose, respectively.…”

Fluorine-containing substituents: metabolism of the α,α-difluoroethyl thioether motif

“…1, are three such compounds that are of commercial significance [8–10]. Metabolism studies in both of these cases show that the major metabolites are their corresponding sulfoxides (Ar–S(O)CF 3 ) and sulfones (Ar–S(O) 2 CF 3 ) [8–9]. Indeed, in the case of the insecticide fipronil it is actually the sulfoxide (Ar–S(O)CF 3 ) that is marketed as the active component [11–12].…”