The effect of caffeine ingestion on pharmacokinetics of caffeine and its metabolites after a single administration in pregnant rats.

Abstract

The pharmacokinetics of caffeine and its metabolites were studied in pregnant rats in order to clarify the effects of maternal caffeine ingestion on the caffeine disposition. On gestational day 18 the single intravenous or oral 10 mg/kg dose of caffeine was administered to pregnant rats who had received drinking water containing 0.04% caffeine or water ad lib during the premating and/or pregnant periods. Concentrations of caffeine and its dimethylxanthines were simultaneously determined by high-performance liquid chromatography. The caffeine plasma concentration-time curves were analyzed by assumption of a one-compartment model. The apparent volume of distribution of caffeine in rats given caffeine only during pregnancy was decreased. The elimination rate constant (kel) of caffeine in most of the rats taking caffeine during pregnancy was increased. The rats which had received caffeine throughout the premating and pregnant periods had a relatively high total body plasma clearance (CL) of caffeine. The kel and the CL widely varied in the rats taking caffeine during pregnancy. The individual values of kel or CL in pregnant rats were significantly correlated with the molar concentration ratios of the metabolites to caffeine in plasma at 8 h after administration of caffeine. It is concluded that the caffeine disposition is influenced by the different modes of maternal caffeine ingestion during the premating and/or pregnant periods.

Effects of Maternal Caffeine Ingestion on the Perinatal Cerebrum

“…Many studies have been per formed on the effects of maternal caffeine ingestion on various reproductive, terato genic and developmental characteristics in rats [1,2] and humans [3,4], However, even now, whether or not and if so how maternal caffeine ingestion is a risk factor in the de velopment of offspring is a matter of discus sion. In a previous study we demonstrated the adverse effect of maternal caffeine inges tion on the fetal cerebrum in the rat, which may be associated with the decreased appar ent volume of distribution of caffeine in ma ternal plasma and the high caffeine content of fetal cerebrum [5][6][7]. In the present study a low level of maternal caffeine consumption was maintained and an attempt was made to elucidate the factors related to cerebral func tion.…”

“…The progres sive reduction in birth weight of offspring of successive pregnancies with caffeine [I], and the higher caffeine and theophylline levels in fetuses in the c-c group than in the W-c group with 0.02 % caffeine, and the almost complete lack of metabolizing capacity for caffeine of the cerebrum for 4-5 h after birth found in the present study suggest some cumulative effect in the offspring from caffeine-treated moth ers. As to the effect of caffeine or theophylline on blood flow in the fetus, several findings may lead to further studies: fetal growth retar dation in the rat due to reduced uterine blood perfusion after gestational day 17 [16], marked relaxation of small human placental arteries caused by theophylline in vitro [17], significant reduction in cerebral perfusion caused by caffeine in man [18], and the de creased apparent volume of distribution of caffeine in maternal plasma on gestational day 18 in the rat caused by caffeine ingestion dur ing pregnancy [6,7], Although no constant relationship between fetal cerebral weight and cerebral caffeine level was recognized (table II), based on the results of our study using 0.04% caffeine [6] and this one using 0.02% caffeine, it is easy to consider that the reduced fetal cerebral weight may be associated with the conditions showing the high caffeine con tents in the mother and fetus.…”

“…The concentrations of caffeine, theophylline, paraxanthine and theobromine were determined essen tially by the methods of Bonati et al [8] and Tse et al [9], with minor modifications as described previously [6,7). Briefly, after extraction with chloroforrmisopropyl alcohol (75:25, v/v), a sample in 0.005 M sodium acetate buffer, pH 5, was injected into a 10-pm pBondapak C|8 column, with a mobile phase of 0.005 M sodium acetate buffer (pH 5):mcthyl alcohol:acetonitrile:tetrahydrofuran (92.5:3:2.8:1.7, v/v).…”

Maternal Caffeine Ingestion Increases the Tyrosine Level in Neonatal Rat Cerebrum

“…The effects of three modes of maternal oral ingestion for dams were about the same as described previously [2][3][4], The litter size was 11 ± 4 [8] in the W-W, 11 ± 2 [9] in the W-C and 11 ± 3 [11] in the C-C group, respectively (means ± SD [no of dams]). The mean body, cerebrum and liver weights of the neonatal offspring are shown in ta ble 1.…”

In Vitro–In Vivo Correlation for Low-Clearance Compounds Using Hepatocyte Relay Method

“…5 for dogs with the corrected concentration (C corrected ) discussed earlier (Hosea et al, 2009). (Nakazawa et al, 1985) 3.0 6 0.76 1.4 Tolbutamide 9.9 (Ashforth et al, 1995;Mandula et al, 2006) 9.8 6 0.71 0.61 Antipyrine 6.5 (Belpaire et al, 1990) 2.4 6 1.35 2.7 Famotidine 9.4 (Matsuzaki et al, 2008) 6.6 6 2.31 1.4 (6)-Warfarin 19 (Yacobi and Levy, 1977;Hirate et al, 1990) 12 6 0.01 1.6 Ranitidine 20 (Eddershaw et al, 1996) 18 6 0. In vivo intrinsic clearance was calculated using the well-stirred model (Ashforth et al, 1995) (eq.…”