Abstract
Purpose: Compare the precision of doxycycline quantification in tear fluid collected with either Schirmer strips or polyvinyl acetal (PVA) sponges following oral drug administration.Methods: Three dogs and 3 cats were administered doxycycline orally at a dose of 4.2–5 mg/kg every 12 h for 6 consecutive days. At day 5 and 6, blood and tear fluid were sampled to capture doxycycline trough and maximal concentrations. Tear fluid was collected 3 times (spaced 10 min apart) at each session with the absorbent material placed in the lower conjunctival fornix until the 20-mm mark was reached (Schirmer strip, one eye) or for 1 min (PVA sponge, other eye). Tear extraction was performed with either centrifugation or elution in methanol. Doxycycline concentrations were measured with liquid chromatography–mass spectrometry. Low (100 ng/mL) and high (1,000 ng/mL) tear concentrations measured in vivo were spiked into each absorbent material in vitro to evaluate percentage drug recovery.Results: After oral administration of doxycycline, the drug reached the tear compartment at concentrations of 45.1–900.7 ng/mL in cats and 45.4–632.0 ng/mL in dogs, representing a tear-to-serum ratio of 12% and 16%, respectively. Doxycycline tear concentrations were significantly more precise when tear collection was performed with Schirmer strips rather than PVA sponges (P = 0.007), but were not correlated with tear flow rate. In vitro doxycycline recovery was poor to moderate (<75%).Conclusions: Schirmer strips represent a good option for lacrimal doxycycline quantification, although the collection and subsequent extraction have to be optimized to improve drug recovery.
Highlights
Administered medications are used to manage a variety of ocular surface diseases across species, for instance oral cetirizine for allergic conjunctivitis in humans,[1] famciclovir for herpetic keratitis in cats,[2] and doxycycline for keratomalacia in horses,[3] among others
This is exemplified by doxycycline, a broad-spectrum antibiotic that has been shown to reach the tear compartment in various species: After oral administration, doxycycline tear concentrations were relatively high in horses (1,810–9,830 ng/mL),[11] lower in cats (100–110 ng/mL),[12] much lower in dogs (0.04–5.73 ng/mL),[13] and nonexistent in humans.[14]
Comparison of tear doxycycline levels between dogs versus cats, and between Ctrough versus Cmax were performed with the Kruskal–Wallis test followed by Dunn’s pairwise comparison, taking into account the following 4 collection/extraction methods: (1) Schirmer strip/centrifugation, (2) Schirmer strip/ methanol elution, (3) polyvinyl acetal (PVA) sponge/centrifugation, and (4) PVA sponge/methanol elution
Summary
Administered medications are used to manage a variety of ocular surface diseases across species, for instance oral cetirizine for allergic conjunctivitis in humans,[1] famciclovir for herpetic keratitis in cats,[2] and doxycycline for keratomalacia in horses,[3] among others. The prerequisite for such therapies is a deep understanding of the drug pharmacokinetics–pharmacodynamics at the ocular surface,[4] a process that first requires accurate quantification of the drug levels in the tear fluid. Under- or overestimating tear concentrations could cause a drug to be given at an inappropriate dose and/or frequency, thereby affecting its efficacy, increasing the risk for drug toxicity, or development of acquired resistance (for anti-infective drugs).[5,6]. The subtle species differences in plasma protein binding of doxycycline[15] cannot solely explain the large discrepancies in the observed tear concentrations; rather, it is likely that the concentrations obtained have been skewed by an unrecognized impact from the tear collection process, as is the case for tear protein content[16] and other analytes like glucose,[17] and warrants further investigation
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