Long-term and per rectum disposition of Clarithromycin in the desert tortoise (Gopherus agassizii)

Abstract

The macrolide antibiotic clarithromycin (CLARI) has a wide spectrum of activity and efficacy for Mycoplasma species. In addition, CLARI accumulates during re-dosing of Mojave desert tortoises (Gopherus agassizii). Here, we characterized plasma concentrations after a single dose, after 3.5 months of dosing, and after per rectum administration; all doses were 15 mg/kg. After a single dose, the median maximal plasma concentration (Cmax) was 1.69 mg/ml and occurred at a median of 6 h after administration, the estimated elimination half-life was 6.9 h, and the median accumulation index was 10%. Plasma concentrations after long-term dosing showed consistent intraturtle concentrations of at least 2 microg/ml, with 1 turtle showing increasing accumulation of CLARI at all 3 time points and the remaining 5 turtles showing increases by 3.5 mo. Compared with expected Cmax values, the median long-term values were approximately 3 times higher than expected in 4 of 6 turtles and approximately 2/3 of that expected in the remaining 2 turtles. Per rectum dosing caused antibiotic retention below target values. Together, these results support accumulation of CLARI after repeated oral dosing and indicate that stable concentrations are reached long-term. Either cystoenteric recycling of CLARI or large intestinal absorption of bypass CLARI may explain the observed cumulative increases. In addition, twice-weekly CLARI maintains target concentrations over time, and per rectum dosing will require higher doses or increased dose frequency to be successful. Based on this work, pharmacokinetic studies in exotic species should include multidose studies to verify initial kinetic estimates from single-dose trends.

Figure 1.

Plasma CLARI concentrations in 6 tortoises (designated B through G) after a single oral dose of 15 mg/kg. Although plasma concentrations declined as expected overall, the shape of individual curves varied considerably, suggesting either a delay in absorption or tissue drug retention followed by slow release into the blood.

Figure 2.

Blood samples were collected at 3 time points during 6 mo of antibiotic administration of twice-weekly oral CLARI at 15 mg/kg. Over the period of administration, plasma concentrations either reached plateau or increased. The median values increased as shown, reflecting a generally increasing trend. Values at 0.5, 2.5, and 3.5 mo ranged from 1.02 to 11.17, 2.37 to 6.67, and 2.28 to 9.48 μg/ml plasma, respectively (n = 6, designated B through G).

Figure 3.

Plasma concentrations of CLARI based on per rectum dosing of 7 tortoises. Five tortoises are shown after treatment with 15 mg/kg every 12 h for the first 3 doses (to 36 h), followed by the same dose delivered daily until day 8. In 2 animals (tortoises 5 and 6), concentrations of CLARI rose above the limit of detection at only 1 point each, so their data were not included in the graph.