Pharmacokinetics of doxycycline in sheep after intravenous and oral administration

Abstract

The pharmacokinetics of doxycycline were investigated in sheep after oral (PO) and intravenous (IV) administration. The IV data were best described using a 2-(n = 5) or 3-(n = 6) compartmental open model. Mean pharmacokinetic parameters obtained using a 2-compartmental model included a volume of distribution at steady-state (V ss ) of 1.759 ± 0.3149 L/kg, a total clearance (Cl) of 3.045 ± 0.5264 mL/ kg/min and an elimination half-life (t 1/2b ) of 7.027 ± 1.128 h. Comparative values obtained from the 3-compartmental mean values were: V ss of 1.801 ± 0.3429 L/kg, a Cl of 2.634 ± 0.6376 mL/kg/min and a t 1/2b of 12.11 ± 2.060 h. Mean residence time (MRT 0À1 ) was 11.18 ± 3.152 h. After PO administration, the data were best described by a 2-compartment open model. The pharmacokinetic parameter mean values were: maximum plasma concentration (C max ), 2.130 ± 0.950 lg/mL; time to reach C max (t max ), 3.595 ± 3.348 h, and absorption half-life (t 1=2k 01 ), 36.28 ± 14.57 h. Non-compartmental parameter values were: C max , 2.182 ± 0.9117 lg/mL; t max , 3.432 ± 3.307 h; F, 35.77 ± 10.20%, and mean absorption time (MAT 0-1 ), 25.55 ± 15.27 h. These results suggest that PO administration of doxycycline could be useful as an antimicrobial drug in sheep.

Population pharmacokinetics of doxycycline in the tears and plasma of northern elephant seals (Mirounga angustirostris) following oral drug administration

“…This Cmax is similar to that reported for sheep (2.13 ± 0.95 µg/mL), 5 although the Tmax was longer in these northern elephant seals (6.1 hours) than in sheep (3.6 ± 3.3 hours). 5 In the present study, doxycycline was administered with food to best replicate the clinical situation in this species, for which temperament precludes manual pill administration. However, in other species, feeding concurrent with doxycycline administration has been shown to alter drug bioavailability.…”

“…The elimination route of doxycycline is unknown in elephant seals and was not determined in the present study. However, the Cl/F of doxycycline in these northern elephant seals was 5.6 to 13.3 mL/ kg/min (2.5 to 6.0 mL/lb/min), which is faster than the reported clearance in sheep (2.6 to 3 mL/kg/min [1.2 to 1.4 mL/lb/min]), 5 a similarly sized mammal. By comparison, the elimination half-life calculated in northern elephant seals following oral administration of a single dose of 20 mg of doxycycline/kg (6.5 hours) was similar to that in sheep (7.0 hours) receiving a single IV dose of 20 mg of doxycycline/kg.…”

“…By comparison, the elimination half-life calculated in northern elephant seals following oral administration of a single dose of 20 mg of doxycycline/kg (6.5 hours) was similar to that in sheep (7.0 hours) receiving a single IV dose of 20 mg of doxycycline/kg. 5 The similar elimination halflife in these 2 species despite apparently faster clearance in northern elephant seals is likely explained by the larger volume of distribution observed in northern elephant seals versus sheep because elimination halflife is dependent on both distribution and elimination.…”

“…17 Indeed, the apparent volume of distribution (as a function of bioavailability) determined in northern elephant seals in the present study (4.0 to 7.1 L/kg [1.8 to 3.2 L/lb]) was large, especially in comparison to values for similarly sized mammals such as adult sheep (1.8 L/kg [0.8 L/lb]). 5 This large volume of distribution most likely occurs because doxycycline distributes into the elephant seals' subcutaneous fat (blubber), which is much thicker than that of terrestrial species. However, this comparison must be interpreted with caution because the oral bioavailability of doxycycline in northern elephant seals is not known.…”

“…4 Furthermore, doxycycline is frequently administered to pinnipeds and has a broad spectrum of activity against Chlamydia spp, Mycoplasma spp, Rickettsia spp, aerobic and anaerobic Gram-positive and -negative bacteria, Brucella spp, Bartonella spp, and Leptospira spp, among others. 5,6 Pinnipeds are commonly infected with many of those important and often zoonotic pathogens, particularly those in the genera Leptospira, Brucella, and Bartonella, [7][8][9][10][11] making doxycycline a justifiable antimicrobial choice in many instances. We hypothesized that doxycycline concentrations achieved in the tears and plasma of seals receiving 20 mg of doxycycline/kg (9.1 mg of doxycycline/lb) every 24 hours for 4 days would meet or exceed those necessary to have clinically relevant antimicrobial effects systemically and within the tear film as well as anti-inflammatory and antiprotease activity at the corneal surface.…”