Metabolism and distribution of labeled theophylline in the pregnant rat. Impairment of theophylline metabolism by pregnancy and absence of a blood-brain barrier in the fetus.

Abstract

Summary: Theophylline was shown to cross the placenta and to be distributed after 1 h among the organs of the fetus and the pregnant rat except for the brain. Lower radioactivity was found in the central nervous system of the pregnant rat compared to the other organs and particularly the brain of the fetus. The blood-brain barrier was observed for theophylline in the adult rat. The degree of exposure of the fetal brain is shown to be twice that of the adult brain. The total absence of a blood-brain barrier for the fetus is thus demonstrated. A ratio of brain to blood theophylline concentration of 0.40 and 0.87 was found respectively for the pregnant rat and the fetus. The presence of a blood-brain barrier observed in the rat cannot be extrapolated to the human. Either the absence or a less efficient blood-brain barrier in the human fetus and neonate has to be taken into consideration. After theophylline administration to pregnant asthmatic women, some of the neonates displayed clinical symptoms that may have been related to placental transfer of theophylline (7, 37).The ability of rat fetus to methylate theophylline into caffeine is demonstrated. Traces of caffeine are produced in utero that may be explained by the absence of theophylline accumulation in the fetus.Urinalysis of the metabolites showed that unchanged theophylline amounted to 73 ± 6% of total urine radioactivity in the pregnant rat as compared to 35 ± 3% in the non-pregnant animal. This impairment of theophylline metabolism in late pregnancy is explained by the decreased formation of 1,3-dimethyluric acid (−68%). The production of 1-methyluric acid was less affected (−30%). Modification of theophylline metabolism during human pregnancy has never been studied. Although 1,3-dimethyluric is the most important theophylline metabolite both in the rat and man, there are such important species differences in the quantitative metabolic pathways that it is important to show whether or not the results obtained from rat studies can be extrapolated to the human.Speculation: In the human, the exposure of the fetus to impaired theophylline metabolism during pregnancy or the absence of a blood-brain barrier could explain clinical symptoms of neurotoxia observed in the neonate when theophylline was administered to pregnant women.