The pharmacokinetics of oxytetracycline in Atlantic cod (Gadus morhua)

Vatcher, Susan L. (1999) The pharmacokinetics of oxytetracycline in Atlantic cod (Gadus morhua). Masters thesis, Memorial University of Newfoundland.

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Abstract

Under conditions of intense fish culture it may be necessary to use antibiotics in order to mitigate disease problems. In an effort to reduce the impact of antibiotic residuals on the environment and to eliminate the risk of exposure of these residuals to the consumer optimal treatment regimes must be developed. These regimes must account for the use of different antibiotics used on a wide range of species held under varying culture conditions. Culture of the Atlantic cod (Gadus morhua) shows a great deal of potential and at present little information is available on the behaviour of Oxytetracycline (OTC) in this species. -- In an effort to generate baseline pharmacokinetic numbers and to determine the clearance time from organs for OTC in Atlantic cod two experiments were undertaken. Experiment 1 examined the pharmacokinetics of OTC in Atlantic cod following a single dose by oral gavage (Per Os (PO)) or intraperitoneal (IP) injection. Eighteen fish were held at 10°C and administered OTC either intraperitoneally a dose level of 132.8 mg OTC/ kg fish or orally at a dose level of 134.5 mg OTC/ kg fish. Blood samples were taken at 0.5, 3, 6, 12, 36 and 72 hrs and analyzed for OTC levels using High Pressure Liquid Chromatography (HPLC). Noncompartmental modeling identified a time to maximum serum concentration (Tmax) for IP and PO administration of 18 hrs and 6 hrs respectively. The shorter Tmax in the PO group as compared to the IP group is not as expected and may have been the result of precipitation in the injectable solution. Maximum serum concentrations (Cmax) for IP and PO were 140.8 ppm and 1.04 ppm respectively. The higher Cmax in the IP group is as expected and both numbers are in the same order of magnitude as literature values. The relative bioavailability of OTC was calculated to be 0.8%. This low value compares well with literature values for orally administered drugs. T½ for PO administration was calculated to be 184 hours. The PO T½ value was then used to predict a clearance time for OTC of 38.3 days from the serum and 55.5 days from the muscle of cod. This number compares well with literature values and with results from experiment 2. -- Experiment 2 examined the absorption, distribution and elimination of oxytetracycline from Atlantic cod held in seawater at temperatures of 10°C and 10°C decreasing to 2°C. Fish were administered OTC in the feed at a dose level of 120 mg OTC/ kg fish over an 11 day period. One group of five fish were held as controls and fed nonmedicated feed. The water temperature for half the medicated fish was maintained at 10°C and for control fish and the other half of the medicated fish was decreased from 10°C to 2°C by daily increments of 0.1°C. Samples of blood, muscle, gonad and liver were taken on days 1, 5, 10, 20, 41, 61 and 101 and analyzed for OTC levels using HPLC. OTC in the gonad was detected in one sample on day 1 only therefore no subsequent statistical analysis was conducted. Data for the remaining three tissue types was grouped by sample day and temperature regime. OTC concentration for the tissue types was plotted versus time. A two factor analysis of variance showed no significant differences in OTC concentrations between the temperature groups for serum, muscle or liver. Lack of a temperature effect on antibiotic clearance is unusual in poikilothermic animals and does not compare with results found in the literature. Insufficient differences in water temperature between the two groups, as a result of small daily incremental decreases, are believed to account for this result. -- There were significant differences in OTC concentration by sample day in the serum, muscle and liver. A Scheffes multiple comparison determined that in serum and muscle the differences were between OTC levels up to and including day 10 and OTC levels on and after day 20. In liver the differences lay between OTC levels up to and including day 41 and OTC levels on and after day 61. It was determined that clearance of OTC in both temperature groups occurred in the serum between day 20 and day 41. This compares well with the predicted value from experiment 1 of 38.3 days. Clearance from the muscle in both temperature groups occurred between day 41 and day 61. This compares well with the predicted value from experiment 1 of 55.5 days. Clearance from the liver in both temperature groups was still occurring up to day 101. -- These results indicate that residuals of OTC in cod for both temperature groups fell below the legally acceptable level of 0.1 ppm by day 41 in the serum and day 61 in the muscle. These fall within the suggested withdrawal period of 80 days, at or above 10°C, for OTC in salmon. They also indicate that a withdrawal period for OTC of 80 days may be acceptable in cod held below 10°C. Clearance of OTC from the liver was not consistently below legal limits in either temperature group within the sample period. This indicates that when harvesting the liver of cultured cod extended clearance times should be considered.

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