The pharmacokinetics of chlortetracycline in turkeys

Pollet, Robert
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Chemical and Biological Engineering

The pharmacokinetics of chlortetracycline (CTC) were studied in healthy and diseased (fowl cholera) turkeys. Because the presence of metal cations in the gastrointestinal tract can inhibit absorption, the effect a metal chelator (citric acid) has on absorption was investigated. The concentration profiles in the plasma and tissues were adequately simulated by a physiologically based model;The relationship between plasma level and dose was evaluated by orally introducing 10, 15, and 20 mg CTC/kg. At these dosage regimens, the areas under the concentration-time curves were nearly linearly related to the dose. A tissue distribution study (15 mg CTC/kg orally) indicated that concentrations of CTC are considerably higher in the liver and kidney than in the muscle and brain;Based on model simulations, the fractions of dose eliminated by renal excretion, biliary secretion, and chemical decomposition are 50%, 46%, and 4%, respectively. The low values of the permeabilities, relative to the regional plasma flows, indicate that tissue permeability limits CTC distribution;The addition of citric acid (150 mg/kg) to an oral CTC (15 mg/kg) mixture (containing 0.3 g/l Ca('2+), 0.1 g/l Mg('2+)) produced significantly higher plasma levels than when citrate was omitted. Citric acid appears to enhance absorption by binding to metal cations and thereby preventing their interference with CTC; consequently, when the amount of minerals in the fowl's gastrointestinal tract was minimized, citric acid had little effect on absorption. The model adequately described plasma profiles of CTC following the coadministration of CTC + citric acid; the addition of citric acid to a CTC mixture increases the unbound fraction of CTC in the lumen from 0.34 to 0.98, and the fraction of dose absorbed from 0.06 to 0.16;When CTC was orally administered to turkeys infected with P. multocida, the infected birds had significantly higher plasma levels than healthy birds. Simulations indicate that these higher plasma levels appear to result from increased gastrointestinal permeabilities coupled with a decrease in hepatic and/or renal clearance.