Omeprazole has been shown to induce cytochrome P450IA1 and P450IA2 activity in vitro. To reflect cytochrome P450IA2 (CYP1A2) activity in vivo, the 13C-[N-3-methyl]-caffeine breath test was conducted in 18 volunteers: 12 extensive metabolizers, one intermediate metabolizer, and five poor metabolizers of S-mephenytoin. Breath tests were performed before treatment with an oral dose of 40 mg omeprazole, on the seventh day of treatment, and after a 7-day washout period. The mean percentage exhalation of the 13C test dose, as determined by 13CO2 in breath during 8 hours, was 23.0% +/- 8.0% (n = 18) before treatment. The largest increases in exhalation rate of 13CO2 were observed in the poor metabolizers and the intermediate metabolizers (range, 12.8% to 62.9%; median, 38.9%); median area under the plasma concentration-time curves (AUC) of omeprazole was four times higher than in the extensive metabolizers. The change after omeprazole treatment in extensive metabolizers ranged from -9.8% to +47.7% (median, 12.3%; n = 12) of pretreatment values. In both groups exhalation rates of 13CO2 returned to near pretreatment values within the 7-day washout period (24.2% +/- 7.8%; n = 17). Changes in the 13C-caffeine breath test correlated well with both the pretreatment value (R = -0.67, p = 0.003; n = 18) and the plasma AUC of omeprazole (R = 0.61, p = 0.007; n = 18). Therapeutic doses of omeprazole seem to induce CYP1A2 activity in poor metabolizers, whereas they exert minor inducing effects in extensive metabolizers of S-mephenytoin.
After obtaining evidence that tetratogenic effects were operant in a sample of children born to epileptic mothers, we analyzed the effects of type of medication and further influential factors. Children with prenatal exposure to polytherapy had significantly lower scores than controls for a large number of psychological tests. In addition to polytherapy, there were even stronger effects of socioeconomic status and sex was found to be less influential than polytherapy. Among further epilepsy variables, only seizure frequency of the mother during pregnancy had a modest impact on the child's developmental outcome, whereas a score of obstetric abnormality was less effective in predicting developmental outcome, as measured and defined by various standardized psychological tests.
To assess toxicokinetics of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), oral intake and fecal excretion were measured in two breast-fed infants and one formula-fed infant during the 1st y of life. The intake of these compounds was up to 50 times higher in the breast-fed infants. In these children, fecal excretion of the main tetra- to hexachlorinated congeners was less than 9% of the intake at age of 1 and 5 mo, indicating almost complete intestinal absorption during breast-feeding. In contrast, distinctly higher fecal excretion rates were observed for the hepta- and octachlorinated compounds. Despite much lower PCDD/PCDF intake after weaning, concentrations in stool fat did not decrease substantially. We conclude that concentrations in fecal fat more or less reflect those in body fat. Additionally, PCDD/PCDF concentrations were measured in blood fat of all infants (and in a second formula-fed baby) at the age of 11 mo. International toxicity equivalent (I-TEq) concentrations in the formula-fed infants were less than 25% of maternal values and about 10 times lower than in the infants breast-fed for 6-7 mo. In the latter, a distinct accumulation was found for the tetra- to hexachlorinated congeners compared with maternal concentrations. We conclude that accumulation of PCDDs and PCDFs in infants is as high as expected on the basis of intake data and assuming complete absorption and negligible elimination during the 1st y of life.
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