Influence of Hypercapnia and/or Hypoxemia and Metabolic Acidosis on Theophylline Kinetics in the Conscious Rabbit1–3

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Abstract
This study investigated the effect of acute changes in blood gases and pH on theophylline kinetics. Groups of 6 conscious rabbits were exposed to air (control) or to a high CO2and/or low O2 atmosphere for 570 minutes, or received 47 ml/kg of 0.3N HCl by gavage. Once blood gases or pH were stabilized, they received 2.5 mg/kg theophylline intravenously. Urine, blood samples, and cerebrospinal fluid were collected. Metabolic acidosis did not modify theophylline kinetics. Theophylline serum concentrations increased with hypercapnia (p < 0.05), hypoxemia (p < 0.01), and hypercapnia combined with hypoxemia (p < 0.001), compared with those in control animals. These increases were related to a decrease in theophylline nonrenal clearance (Clnr). Thus, Clnr decreased from 1.52 ± 0.05 ml/min/kg in control animals to 1.13 ± 0.13 in hypercapnia (p < 0.01), 1.09 ± 0.09 in hypoxemia (p < 0.001), and 1.02 ± 0.02 in hypoxemia combined with hypercapnia (p < 0.001). Theophylline protein binding was not affected by any of the experimental conditions. The ratio of central nervous system to serum theophylline concentration was increased by 16% (p < 0.05) with hypercapnia combined with hypoxemia. It was concluded that both hypercapnia and/or hypoxemia decreased theophylline biotransformation. Such a decrease may be the cause of toxicity.