Diltiazem blood pharmacokinetics in the pregnant and non-pregnant rabbit: maternal and foetal tissue levels

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Abstract
1. The aim was to investigate the pharmacokinetics of diltiazem (DTZ) and its metabolites, deacetyldiltiazem (M1) and N-demethyldiltiazem (MA), in the pregnant rabbit following DTZ intravenous administration. In addition, DTZ tissue distribution in both the non-pregnant and pregnant rabbit and foetuses was also studied. 2. The slope of the alpha- and beta-phases increased slightly in six of the eight pregnant rabbits as compared with the non-pregnant animal, but the other pharmacokinetic parameters that largely determine drug disposition (AUC, V(n), CL) showed no significant differences. 3. MA blood disposition was unaltered by pregnancy. However, all the pharmacokinetic parameters calculated for the deacetylated metabolite of DTZ were significantly modified in the pregnant as compared with the non-pregnant rabbit. 4. DTZ tended to concentrate in most of the tissues examined. Significant differences were observed in the DTZ concentration in the uterus and kidney from the pregnant as compared with the non-pregnant rabbit. 5. The findings suggest that DTZ diffuses easily through the placenta, reaching DTZ blood concentrations equivalent to that observed in maternal blood. However, the concentration of DTZ and its metabolites in the selected foetal tissues was either higher (in brain and muscle) or lower than that observed in maternal tissues, suggesting a different tissue affinity and/or a different metabolic activity in the foetuses as compared with the mothers.