Butafosfan: a phosphorus source for animals

Butafosfan is an organic phosphorus supplement that is given, most commonly with cyanocobalamin, to cattle, swine, horses, and poultry for the prevention or treatment of deficiencies. When given with cyanocobalamin, butafosfan alters lipid metabolism, serving to decrease the prevalence of subclinical ketosis.

Pharmacokinetics of butafosfan

Butafosfan, a compound of organic phosphorus, is not only used as a phosphorus source for animals but also plays a vital role in hepatic carbohydrate metabolism. In addition, butafosfan has been regarded as an antistress agent in combination with vitamin B12. Studies with butafosfan in different animals have shown that it improved general health status by stimulating feed intake, immune system, and digestive function. Butafosfan has been reported for the treatment of metabolic disorders caused by stress or nutrition problems in various species. However, no specific information about the pharmacological activities and pharmacokinetic profiling of butafosfan has been reported previously. To author's knowledge, it was only referred in an abstract reported by European public MRL assessment report (EPMAR) of butafosfan, where many parameters were not put forward. In this study, the pharmacokinetics and bioavailability of butafosfan were conducted in piglets after intravenous (i.v.) and intramuscular (i.m.) administrations to recommend a rationalized and scientifically sound dosage regimen.[1]

Catosal, the sterile injectable solution, contains 10% butafosfan. This compound was provided by Bayer HealthCare LLC Animal Health Division. The drug was given in the neck behind the ear for intramuscular (i.m.) injection and the ear vein for intravenous (i.v.) injection with the same dosage of 10 mg butafosfan/kg body weight. Sixteen clinically healthy crossbred weaning piglets (one or two weeks old), weighing approximately 10 kg, were purchased and housed in animal house of National Center for Veterinary Drug Safety Evaluation. Prior to the experiment, they were accommodated for one week with commercial standard diets and accessible to water ad libitum. Experiments referring to animals were conducted according to the Guidelines of China Agricultural University (Beijing, China) concerning the protection of animals used for scientific purposes (2010-SYXK-0037). The piglets were randomly arranged into two groups (eight pigs in each group). A crossover design with a 7-day washout period was adopted to investigate the pharmacokinetic profiles of butafosfan. For i.v. and i.m. administration, blood samples were gathered from anterior vena cava prior to and 0.08, 0.16, 0.33, 0.5, 0.45, 1, 2, 3, 4, 6, 8, 12, 24, and 36 h after injection. The samples were collected into heparinized tubes and centrifuged at 1867 g for 10 min. Because not all the samples were analyzed on the same day, the plasma samples were stored at −20 °C until analysis.

After i.v. administration, the mean values of T1/2λz and Cl were 3.30 h and 0.16 L kg/h, suggesting the rapid elimination of butafosfan after i.v. injection in piglets. The Vss was 0.81 ± 0.44 L/kg, indicating that the drug was widely distributed into body tissues. After i.m. administration, the means values of Tmax and F were 0.31 h and 74.69% while the corresponding means values of Cmax and T1/2λz were 28.11 μg/mL and 4.21 h, respectively. From the results showed above, we could draw a conclusion that butafosfan embraced a highly absolute bioavailability and a quick decline in plasma. Furthermore, the mean residence time (MRT) is 1.74 h, showing that butafosfan maintained a short period of time in plasma. Butafosfan is intended for piglets as a supportive therapy. Although the plasma concentrations associated with efficacy have not been determined, the pharmacokinetic characteristics of butafosfan following i.v. and i.m. administration in piglets were acquired in this study, laying the theoretical foundation for the better use of butafosfan.

Effects of Butafosfan on salivary cortisol

Measures to reduce or prevent the consequences of this stress are to keep the animals in ‘stress-free’ housing conditions (Ekkel et al., 1995) or to administer drugs that reduce the adverse effects of stress. One such potential product is Catosal, a veterinary tonic and metabolic stimulant containing Butafosfan and cyanocobalamin (vitamin B12) as pharmaceutically active ingredients. Pigs were injected subcutaneously with Catosal® at a dose equivalent to 20 mg Butafosfan per kg body weight or with a control solution containing all ingredients of Catosal® except Butafosfan, immediately before being housed with an unfamiliar pig. The salivary cortisol response and the frequency and duration of aggressive behavior were measured over the subsequent 2h. [2]

This study corroborates earlier findings that Butafosfan has antistress effects in pigs and is in line with previous observations in cattle and sheep (Simon, 1990). The mode of action of Catosal is not known but it is thought to act centrally. This possibility deserves further investigation at the molecular and endocrine level (i.e. effects of Butafosfan on the hypothalamic, pituitary, adrenal axis). However, it cannot be excluded that Butafosfan acts by reducing overall activity (as reflected by the reduction in the frequency and duration of aggressive encounters, although the latter was not confirmed statistically). There were 24 pairs, each consisting of confronting two unfamiliar pigs in a new pen. This housing of unfamiliar pigs provides a good, but simple, model of the psychosocial stress that pigs experience when housed in large groups on pig farms. Immediately before being housed with an unfamiliar pig, 12 pairs of pigs were injected subcutaneously with Catosal at a dose equivalent to 20 mg Butafosfan per kg body weight; the other 12 pairs received the control solution containing all ingredients of Catosal except Butafosfan.

Effect of butafosfan supplementation during oocyte maturation

Butafosfan is an organic phosphorus molecule that has been used as a metabolic modulator in dairy cows, and may represent an alternative to improve in vitro oocyte competence. Some field reports have suggested beneficial results from butafosfan injection in cattle- and horse-assisted reproduction programmes, although no scientific evidence can be found in the published literature. When associated with cyanocobalamin, butafosfan increased the number of small follicles in cows. Phosphorus is also essential for synthesis of nucleotides related to hormonal signalling and for growth, differentiation and cellular integrity. ATP concentration is higher in muscle and liver tissue of rats treated with butafosfan. Based on these findings, the aim of this study was to evaluate the addition of increasing doses of butafosfan during oocyte maturation in vitro on the initial embryo development in cattle.[3]

Around 60–80% of oocytes maturated in vivo reached competence, while the proportion of maturation in vitro is rarely higher than 40%. In this sense, butafosfan has been used in vivo to improve metabolic condition of postpartum cows, and can represent an alternative to increase reproductive efficiency in cows. The aim of this study was to evaluate the addition of increasing doses of butafosfan during oocyte maturation in vitro on the initial embryo development in cattle. In total, 1400 cumulus–oocyte complexes (COCs) were distributed in four groups and maturated according to supplementation with increasing concentrations of butafosfan (0 mg/ml, 0.05 mg/ml, 0.1 mg/ml and 0.2 mg/ml). Then, 20 oocytes per group were collected to evaluate nuclear maturation and gene expression on cumulus cells and oocytes and the remaining oocytes were inseminated and cultured until day 7, when blastocysts were collected for gene expression analysis. A dose-dependent effect of butafosfan was observed, with decrease of cleavage rate and embryo development with higher doses. No difference between groups was observed in maturation rate and expression of genes related to oocyte quality. Our results suggest that butafosfan is prejudicial for oocytes, compromising cleavage and embryo development.

References

[1]Sun F, Wang J, Yang S, Zhang S, Shen J, Xingyuan C. Pharmacokinetics of butafosfan after intravenous and intramuscular administration in piglets. J Vet Pharmacol Ther. 2017 Apr;40(2):203-205.

[2]Van Der Staay FJ, De Groot J, Van Reenen CG, Hoving-Bolink AH, Schuurman T, Schmidt BH. Effects of Butafosfan on salivary cortisol and behavioral response to social stress in piglets. J Vet Pharmacol Ther. 2007 Oct;30(5):410-6.

[3]Teixeira Hax L, Rincón JAA, Schneider A, Pegoraro LMC, Franco Collares L, Alves Pereira R, Pradieé J, Del Pino FAB, Nunes Corrêa M. Effect of butafosfan supplementation during oocyte maturation on bovine embryo development. Zygote. 2019 Oct;27(5):321-328.

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