Pharmacokinetics of oral chlortetracycline in nonpregnant adult ewes

Abstract

The objectives of this study were to determine plasma concentrations and pharmacokinetic parameters of feed-grade chlortetracycline (CTC) in sheep after oral administration of 80 or 500 mg/head daily, divided into two equal doses given at 12-h intervals for 8 days. These are the approved, and commonly used but unapproved, feed additive doses, respectively, in the United States for the prevention of ovine infectious abortion. Blood samples were collected just prior to dosing at 0, 12, 24, 72, 96, and 192 h, as well as 4, 8, 12, 24, and 36 h after the last dose, and noncompartmental pharmacokinetic analysis was performed to estimate elimination half-life and area under the plasma concentration–time curve (AUC). Mean observed maximum CTC concentrations (Cmax) were 20.0 ng/mL (80 mg dose) and 101 ng/mL (500 mg dose). Mean apparent elimination half-life was 18 h (80 mg dose) and 20 h (500 mg dose). Although published data do not exist to estimate plasma CTC concentrations necessary for the prevention of ovine infectious abortion, concentrations reached in our study suggest that either the FDA-approved and FDA-unapproved dosages are not high enough or that the pharmacodynamic parameter relating preventive dose to pathogen minimum inhibitory concentrations is yet to be determined.

Pharmacokinetics of chlortetracycline in maternal plasma and in fetal tissues following oral administration to pregnant ewes

“…A report of tetracycline in rats demonstrated similar concentrations in fetal and maternal plasma once steady‐state had been reached (Olanoff & Anderson, ). Mean maternal plasma concentrations were consistent with our previous study in nonpregnant ewes (Washburn et al., ). For example, the mean concentration of CTC on Day 7 (Hour 168) of treatment was 109 ± 28 ng/ml, whereas in the previous study, the mean concentration at the same time was 81 ± 30 ng/ml.…”

“…It has been suggested that the feeding of an extra‐label dose of CTC of up to 500 mg/head/day may result in increased efficacy of managing sheep flocks in the last trimester to prevent abortion outbreaks from campylobacteriosis (Menzies, ). However, a recent study by the current investigators (Washburn et al., ) found that plasma levels of nonpregnant sheep fed the unapproved dose of 500 mg/head/day were far below the minimum inhibitory concentrations (MIC) of tetracyclines reported in the literature for most Campylobacter jejuni isolates collected from livestock and isolates associated with abortion outbreaks (Oporto, Juste, & Hurtado, ; Sahin et al., ; Scott et al., ). Further, the extra‐label use of this elevated level of CTC is an illegal usage of a feed additive in the US.…”

“…However, a recent study by the current investigators (Washburn et al, 2014) found that plasma levels of nonpregnant sheep fed the unapproved dose of 500 mg/head/day were far below the minimum inhibitory concentrations (MIC) of tetracyclines reported in the literature for most Campylobacter jejuni isolates collected from livestock and isolates associated with abortion outbreaks (Oporto, Juste, & Hurtado, 2009;Sahin et al, 2008;Scott et al, 2012). Further, the extra-label use of this elevated level of CTC is an illegal usage of a feed additive in the US.…”

“…Liquid samples were processed using a method based on previous work (Washburn et al., ). Two hundred microliters of sample were mixed with 10 μl of 20 ng/μl demeclocycline internal standard and 100 μl of 1 M trichloroacetic acid using a vortex mixer.…”

Pharmacokinetics of tulathromycin in fetal sheep and pregnant ewes

“…Reports of resistance and lack of efficacy have prompted investigation of the pharmacokinetics of the common feed‐additive chlortetracycline. Feeding chlortetracycline to sheep at the approved dose and at the higher, unapproved dose results in subtherapeutic levels in pregnant ewe plasma and mostly undetectable levels in fetal tissues and amniotic fluid (Washburn et al., , ). Chlortetracycline in feed requires a veterinary feed directive, and extra‐label use or use of increased doses of feed additives is illegal in the United States.…”