Antimicrobial disposition in pulmonary epithelial lining fluid of horses, Part II. Doxycycline

Abstract

Doxycycline concentrations, following two types of oral administration to horses, in pulmonary epithelial lining fluid (PELF) were examined and compared to plasma concentrations. The oral bioavailability was estimated from plasma concentrations achieved after an intravenous study in two horses. Doxycycline (10 mg/kg) was administered either intragastric or as topdressing to nonfasted horses. Blood samples were collected for drug analysis, before and 11 times after administration during 24 h. PELF samples were collected by a tampon device four times after drug administration and analysed for doxycycline concentrations. Another two horses received doxycycline intravenously at a dose of 3 mg/kg and plasma was taken 14 times during a 24- h period. The oral bioavailability of doxycycline was calculated to 17% after intragastric administration and 6% after topdressing administration in nonfasted horses. The degree of penetration of doxycycline into PELF, as described by AUC(PELF) /AUC(plasma) ratios, was 0.87 after intragastric administration. The results indicate that clinically relevant doxycycline concentrations are possible to maintain in PELF after intragastric administration. Furthermore, if bioavailability could be enhanced for per os administration, doxycycline might be a valuable drug for the treatment of lower airway infections in horses.

Pharmacokinetics of a peroral single dose of two long-acting formulations and an aqueous formulation of doxycycline hyclate in horses

“…The pharmacokinetics of an aqueous solution of Dox-h administered orally (PO) has been determined in adult horses [1,6,11,12] and in foals [2]. In these studies, Dox-h was administered either dissolved in water via nasogastric tube or as a top dressing at doses ranging from 3 mg/kg to 20 mg/kg every 12 (q12h) or every 24 hours (q24h).…”

“…Yet, Davis et al [6] and Womble et al [2] consider that the therapeutic value of oral Dox-h in adult horses is limited due to its low bioavailability. Winther et al [12] reported an estimated oral bioavailability of Dox-h of 17% after intragastric administration and 6% after topdressing administration in non-fasted adult horses. Similarly, these authors consider that if the oral bioavailability of Dox-h could be enhanced, this antimicrobial drug might be a valuable resource for the treatment of lower airway infections in horses.…”

Antimicrobial drug concentrations and sampling techniques in the equine lung

“…However, both measured clinically relevant drug concentrations for simple streptococcal infections in PELF for 12 h after drug administration. Doxycycline concentrations measured by liquid chromatography-mass spectrometry (LC-MS) in PELF were reported and almost equivalent exposures were found in PELF compared to plasma (Winther et al, 2010b). However, very low oral bioavailability was found for the formulation used (6-17%), making PELF concentrations only clinically relevant for very susceptible pathogens.…”

“…Several studies in horses and other species (including humans) have shown different pharmacokinetics and distribution to the lung compared to plasma, dependent on the drug and the animal species (Agerso and Friis, 1998;Cazzola et al, 2002;Dhanani et al, 2010;Halstead et al, 1992;Nix, 1998;Winther et al, 2010b). This makes it difficult to predict pulmonary drug concentrations over time.…”

“…Manual compression of the swab or centrifuging the disc results in sampling of undiluted PELF secretions for analysis. The limitations of this technique are that only a small volume of sample is obtained, which restricts the analysis (McKellar et al, 1999;Winther et al, 2010b), and that increasing amounts of inflammatory exudate may be collected after multiple sampling, influencing the influx of drug into the secretions (Halstead et al, 1992). Furthermore, since some drugs may adhere to the disc or cotton material, a control laboratory study may have to be undertaken in order to determine the percentage recovery from the absorbent material when exposed to a known drug concentration.…”