Controlled release of tetracycline—III: A physiological pharmacokinetic model of the pregnant rat

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Abstract
A controlled tetracycline delivery device, consisting of a membrane enclosed trilaminate disc fabricated from a series of 2-hydroxyethylmethacrylate/methylmethacrylate copolymers, demonstrated the ability to deliver tetracycline at zero-order rates in vitro and in vivo in rats and was applied to study the pharmacokinetics of tetracycline in the pregnant rat. The trilaminate discs containing tetracycline were implanted in pregnant Sprague-Dawley rats on the eighth day of gestation. The animals were sacrificed on days 19, 20, and 21 of gestation in order to measure the distribution of the controlled release tetracycline in the maternal, fetal, and placental tissues. Constant plasma tetracycline levels were attained in both the maternal and fetal circulations after 4 to 5 days postimplantation of the trilaminate discs. Placental transfer of tetracycline appeared rapid and no partitioning of the drug was observed between the maternal and fetal plasma. Tetracycline levels did not differ significantly in the maternal and fetal soft tissues (liver, kidney, G. I. tract, muscle, placenta) as measured over the last 3 to 4 days of the animal's gestational period. Highest tetracycline concentrations were determined in the fetal bone samples. In addition, some accumulation of the drug occurred in the amniotic fluid. A flow-limited pharmacokinetic model was constructed to simulate the distribution of tetracycline, delivered at a constant rate from the trilaminate device, in the pregnant rats. Predictions of fetal growth and maternal and fetal tissue tetracycline concentrations were in good agreement with the experimental measurements. The ability of these copolymer systems to deliver tetracycline at zero-order rates over extended periods offers numerous potential therapeutic and investigational applications, especially where such drug delivery characteristics are beneficial to the elucidation of physiological rate mechanisms, as in the pregnant animal.