Plasma pharmacokinetics of butyrate after intravenous administration of sodium butyrate or oral administration of tributyrin or sodium butyrate to mice and rats

Purpose: To define the plasma concentrations of butyrate achieved and the p rofile of plasma butyrate concentrations versus time in mice and rats treat ed with tributyrin or sodium butyrate. Methods: Female CD2F1 mice were trea ted with tributyrin by oral gavage or with sodium butyrate by i.v. bolus or oral gavage. Oral tributyrin doses delivered to mice were 3.1, 5.2, 7.8, a nd 10.3 g/kg. Intravenous sodium butyrate doses were 0.31, 0.62, 0.94, and 1.25 g/kg. Oral sodium butyrate was given to mice at 5 g/kg. Subsequently, similar studies were performed in female Sprague-Dawley rats. Rats were giv en tributyrin by oral gavage at doses of 3.6, 5.2, or 10.3 g/kg or sodium b utyrate i.v. at a dose of 500 mg/kg. Plasma butyrate concentrations were de termined by gas chromatography. Results: In mice, oral dosing with tributyr in resulted in detectable plasma butyrate concentrations as early as at 5 m in after treatment and produced peak plasma butyrate concentrations at betw een 15 and 60 min after dosing. Peak plasma butyrate concentrations increas ed proportionally with increasing tributyrin dose, but as the oral tributyr in dose increased there was a greater than proportional increase in the are a under the curve of plasma butyrate concentrations versus time (AUC). At a tributyrin dose of 10.3 g/kg, plasma butyrate concentrations peaked at app roximately 1.75 mM and remained greater than or equal to 1 mM for between 1 0 and 60 min after dosing. However, approximately 10% of mice treated with this dose died acutely. At a tributyrin dose of 7.8 g/kg, plasma butyrate c oncentrations reached approximately I mM by 15 min after dosing and remaine d between 0.8 and 1 mM until 60 min after dosing. No mouse treated with thi s dose died acutely. Mice given tributyrin doses of 5.2 and 3.1 g/kg achiev ed peak plasma butyrate concentrations of approximately 0.9 and 0.5 mM, res pectively, by 45 min after dosing. Plasma butyrate concentrations in these mice remained above 0.1 mM until 120 and 90 min after dosing, respectively. The four i.v. doses of sodium butyrate resulted in plasma concentration-ti me profiles that also indicated nonlinear pharmacokinetics and were well de scribed by a one-compartment model with saturable elimination. Values recor ded for the Michaelis-Menten constant (K-m) and the maximal velocity of the process (V-max) ranged between 1.02 and 5.65 mM and 0.60 and 1.82 mmol/min , respectively. Values noted for the volume of the central compartment (V-c ) varied between 0.48 and 0.72 1/kg. At 1.25 g/kg, i.v. sodium butyrate pro duced peak plasma butyrate concentrations of 10.5-17.7 mM, and plasma butyr ate concentrations remained above 1 mM for 20-30 min. Sodium butyrate deliv ered orally to mice at 5 g/kg produced peak plasma butyrate concentrations of approximately 9 mM at 15 min after dosing and plasma butyrate concentrat ions exceeding 1 mM for 90 min after dosing. In rats the 10.3-g/kg oral dos e of tributyrin produced peak plasma butyrate concentrations of approximate ly 3 mM by 75 min after dosing and butyrate concentrations excedding 1 mM f rom 30 to 90 min after dosing. The plasma butyrate concentrations produced in rats by 5.2- and 3.6-g/kg doses were appropriately lower than those prod uced by the 10.3-g/kg dose, and there was no evidence of nonlinearity. The 500-mg/kg i.v. dose of sodium butyrate produced peak plasma butyrate concen trations in rats of approximately II mM, and the decline in plasma butyrate concentrations with time after dosing was consistent with saturable cleara nce. Conclusion: These studies document the ability to use oral administration o f tributyrin to achieve pharmacologically relevant concentrations of butyra te in rodent plasma. They also document the nonlinear nature of butyrate cl earance. These data are being used in the design of clinical trials of oral tributyrin in patients with malignancies and hemoglobinopathies.