Pharmacokinetics of bromoform in dairy heifers

Abstract

ABSTRACT Aims To determine the pharmacokinetics in dairy heifers after oral and IV administration of bromoform, a potential antimethanogenic agent found in red seaweed, Asparagopsis spp. Methods Twenty-four dairy heifers with a mean weight of 319 (SD 36.9) kg were used. The study was conducted in two phases, and each cohort of 12 heifers received an escalating dose of bromoform. In the first phase, 12 heifers successively received doses of 200, 400, 800, and 1600 mg of bromoform orally, separated by a 72-hour washout period. In the second phase, a different cohort of 12 dairy heifers was used. Each heifer received a total of four doses of bromoform separated by a wash-out period of 72 hours. Sequentially the treatments were (for each of the 12 heifers) an oral dose of 50 mg, followed by an IV dose of 50 mg, followed by an oral dose of 100 mg and finally an IV dose of 100 mg. Blood samples were assayed by gas chromatography-mass spectrophotometry for bromoform and dibromomethane to estimate the pharmacokinetic parameters using a non-compartmental analysis. Results Bromoform was rapidly absorbed as indicated by a short time to the maximum observed concentration of 15 minutes. For the routes of administration and dose ranges investigated, the mean terminal half-life ranged from 0.32 (SE 0.03) hours to 5.73 (SE 1.64) hours when administered orally or IV. With values for the mean area under the curve (AUC) to dose ratio ranging from 0.25 (SE 0.04) to 0.82 (SE 0.19) for oral and 1.39 (SE 0.39) to 4.02 (SE 0.37) for IV administration, bromoform appeared to exhibit non-proportional pharmacokinetic behaviour. The mean absolute bioavailability was 39.13 (SE 10.4)% and 3.36 (SE 0.83)% for 50-mg and 100-mg doses, respectively. Conclusions and clinical relevance Bromoform is rapidly absorbed and exhibits dose dependent elimination kinetics. Abbreviations AUC0–24: Area under the curve from 0 to 24 hours; AUC0–∞: Area under the curve from 0 to infinity; AUMC: Area under the first moment curve; Cl: Clearance; t½: Elimination half-life; Cmax: Maximum observed concentration; Kel: Terminal slope; MRT: Mean residence time; PK: Pharmacokinetic; Tmax: Time of Cmax; Vd: Volume of distribution