Caffeine and its dimethylxanthines and fetal cerebral development in rat

The relationship between the distribution and pharmacokinetic behavior of caffeine and its dimethylxanthines in pregnant rats and fetuses and fetal cerebral development was compared in four groups with different modes of oral caffeine ingestion by the mothers. During the premating period and pregnancy, female Wistar rats were divided into 0.04% caffeine (C) and water (W) groups, respectively. When the groups are expressed as W or C before mating-W or C during pregnancy, the fetal body weight was low in the three caffeine-treated groups (W-C, C-W and C-C) and the fetal cerebral weight was the lowest in the W-C group. The mean concentration of caffeine or metabolites in maternal plasma, maternal liver, placenta and fetal cerebrum on gestational day (g d) 21 was increased in the W-C group compared to in the C-C group. The concentration of caffeine in fetal cerebrum was increased but that of metabolites was not, compared to the concentration of caffeine or metabolites in the placenta. Radioactivity in fetal cerebrum after intraperitoneal injection of 14C-caffeine was higher in the W-C group than in the other three groups. After intravenous injection of caffeine the apparent volume of distribution of caffeine in maternal plasma was markedly decreased in the W-C group, and the plasma molar concentration ratio of theophylline to caffeine was significantly increased in both the W-C and C-C groups. The adverse effect of maternal caffeine ingestion on the fetal cerebrum may be associated with the decreased apparent volume of distribution of caffeine in maternal plasma and the high caffeine content of fetal cerebrum.