Pharmacokinetics of indomethacin in sheep after intravenous and intramuscular administration

Abstract

The pharmacokinetics of indomethacin (1 mg/kg) was determined in six adult sheep after intravenous (i.v.) and intramuscular (i.m.) injection. Plasma concentrations were maintained within the therapeutic range (0.3-3.0 microg/mL) from 5 to 50 min after i.v. and from 5 to 60-90 min after i.m. administration. After two trials, indomethacin best fitted an open two-compartment model. The mean (+/- SD) volumes of distribution at steady state (Vd(ss)) were 4.10 +/- 1.40 and 4.21 +/- 1.93 L/kg and the mean clearance values (ClB) were 0.17 +/- 0.06 and 0.22 +/- 0.12 L/h x kg for i.v. and i.m. routes, respectively. The elimination phase half-lives did not show any significant difference between routes of injection (t1/2beta = 17.4 +/- 4.6 and 21.25 +/- 4.44 h, i.v. and i.m. respectively). After i.m. administration, plasma maximum concentration (Cmax = 1.10 +/- 0.68 microg/mL) was reached 10 min after dosing; the absorption phase was fast (Kab = 26 +/- 18 h(-1)) and short (t1/2ab = 2.33 +/- 1.51 min) and the mean bioavailability was 91.0 +/- 32.8%, although there was considerable interanimal variation. In some individuals, bioavailability was higher than 100%. This fact combined with the slower elimination phase after i.m. than after i.v. administration, could be related with enterohepatic recycling.

Chronobiological variations of indomethacin pharmacokinetic parameters in sheep

“…In the current study, these effects occurred only during those administration times when concentrations were high (approximately 5–6 μg/mL). Distribution was very rapid at every time of administration, as shown by the half‐lives of between 10 and 15 min, and were more rapid at 02:00 h. These values are slower than those reported for sheep (5.11 min; Vinagre et al ., 1998), but similar to those for dogs (19 min; Cociglio et al ., 1991) and humans (18 min; Duggan et al ., 1972).…”

“…Pharmacokinetics of indomethacin after i.v. administration have been described in sheep (Vinagre et al ., 1998), cattle (Cristofol et al ., 1996), dog (Cociglio et al ., 1991) and humans (Duggan et al ., 1972; Friedman et al ., 1991). On the basis of the discrimination criteria they utilized, these authors have presented an open two‐compartment model with first‐order elimination.…”

“…Values higher than 3.0 μg/mL were observed 5 min after administration, regardless of time of injection. Reported side‐effects associated with drug administration in sheep (Vinagre et al ., 1998), humans (Hasan et al ., 1994) and horses (Roberts, 1982) include respiratory distress, apathy and bewilderment. In the current study, these effects occurred only during those administration times when concentrations were high (approximately 5–6 μg/mL).…”

“…Several papers have reported the pharmacokinetics of indomethacin in humans and other species (Hucker et al ., 1966; Alvan et al ., 1975). In ruminant species, plasma pharmacokinetics of indomethacin has been studied after intravenous injection in cattle (Cristofol et al ., 1996) and sheep (Vinagre et al ., 1998).…”

Haemodynamic responses to angiotensin II in conscious lambs: role of nitric oxide and prostaglandins

“…RBF as well as arterial and venous pressures were recorded onto a polygraph (Grass Instruments, model 7, West Warwick, RI, USA) and simultaneously digitized at 200 Hz using the data acquisition and analysis software package, PolyVIEW™ (Astro Med Inc., Grass Instrument Division, West Warwick, RI, USA).Two experiments were carried out on each animal at minimum intervals of 24 h. On the day of the experiment, the animal was pretreated with either vehicle (VEH; experiment 1) or INDO (1 mg kg −1 , experiment 2). Due to the known half-life of INDO in sheep of ∼17 h[45], VEH was always administered first. In each experiment, the pressor and RBF responses to ANG II were measured before (control) and 30 min after administration of the L-arginine analogue, L-NAME (20 mg kg −1 ).…”