The pharmacokinetics of methocarbamol and guaifenesin after single intravenous and multiple‐dose oral administration of methocarbamol in the horse

Abstract

A simple LC/MSMS method has been developed and fully validated to determine concentrations and characterize the concentration vs. time course of methocarbamol (MCBL) and guaifenesin (GGE) in plasma after a single intravenous dose and multiple oral dose administrations of MCBL to conditioned Thoroughbred horses. The plasma concentration-time profiles for MCBL after a single intravenous dose of 15 mg/kg of MCBL were best described by a three-compartment model. Mean extrapolated peak (C0 ) plasma concentrations were 23.2 (± 5.93) μg/mL. Terminal half-life, volume of distribution at steady-state, mean residence time, and systemic clearance were characterized by a median (range) of 2.96 (2.46-4.71) h, 1.05 (0.943-1.21) L/kg, 1.98 (1.45-2.51) h, and 8.99 (6.68-10.8) mL/min/kg, respectively. Oral dose of MCBL was characterized by a median (range) terminal half-life, mean transit time, mean absorption time, and apparent oral clearance of 2.89 (2.21-4.88) h, 2.67 (1.80-2.87) h, 0.410 (0.350-0.770) h, and 16.5 (13.0-20) mL/min/kg. Bioavailability of orally administered MCBL was characterized by a median (range) of 54.4 (43.2-72.8)%. Guaifenesin plasma concentrations were below the limit of detection in all samples collected after the single intravenous dose of MCBL whereas they were detected for up to 24 h after the last dose of the multiple-dose oral regimen. This difference may be attributed to first-pass metabolism of MCBL to GGE after oral administration and may provide a means of differentiating the two routes of administration.

Pharmacokinetics of methocarbamol and phenylbutazone in exercised Thoroughbred horses

“…The detection time and time above the ARCI‐recommended regulatory threshold following administration of both single and multiple doses of 15 g of MCBL were more prolonged in the current study compared with the previous reports that utilized a lower dose (Rumpler et al ., ). Fifteen of sixteen horses exceeded the ARCI threshold recommendation at 48 h (the current recommended withdrawal time guideline) postadministration of the final dose.…”

“…It has been suggested previously that the clearance of MCBL is dose dependent with decreased rates of clearance and a longer elimination half‐life reported as intravenous doses increased from 4.4–17.6 mg/kg (Muir et al ., ). The elimination half‐life for the 15 g dose was within the range of that reported previously (Rumpler et al ., ) and was not significantly different from that determined for horses that received a single 5 g dose in the current study. Furthermore, the elimination half‐life was not significantly different between horses that received a single 15 g dose and those administered multiple 15 g oral doses followed by a single IV administration, suggesting that elimination is still first order following oral administration of doses ranging from 5–15 g. These findings along with a similar absorption half‐life between the groups indicate that the difference in the time above the recommended regulatory threshold is simply due to higher drug exposure as a result of higher dose administration.…”

“…The systemic clearance and elimination half‐life following a single 2 g intravenous dose was in close agreement with that previously reported for a single intravenous dose of 15 mg/kg (Rumpler et al ., ). Similarly, the elimination half‐life following a single 5 g oral dose in the current study was in agreement with that reported previously for a single oral dose of 5 g (Cunningham et al ., ; Rumpler et al ., ). Following administration of a single intravenous dose of 2 g or a single oral dose of 5 g, serum concentrations fell below both the USEF‐ and RMTC‐recommended regulatory threshold by the recommended withdrawal times.…”

“…The pharmacokinetics of MCBL have been described previously (Muir et al ., , ; Cunningham et al ., ; Rumpler et al ., ). An elimination half‐life of 1.68 (Cunningham et al ., ) and 2.89 h (Rumpler et al ., ) has been reported previously for oral administration and 2.96 h for intravenous administration (Rumpler et al ., ).…”

“…The pharmacokinetics of MCBL have been described previously (Muir et al, 1984(Muir et al, , 1992Cunningham et al, 1992;Rumpler et al, 2014). An elimination half-life of 1.68 (Cunningham et al, 1992) and 2.89 h (Rumpler et al, 2014) has been reported previously for oral administration and 2.96 h for intravenous administration (Rumpler et al, 2014). However, elimination of MCBL is reportedly dose dependent in horses (Muir et al, 1984), and therefore, the potential for a positive regulatory finding in performance horses exists if doses in excess of those recommended by USEF and ARCI are utilized.…”