Placental transfer and tissue distribution of thiopental in the pregnant rat

Abstract

The pharmacokinetic profile of thiopental was studied in pregnant rats after an iv bolus dose of 15 mg/kg. The unbound concentration-time profile of the drug in maternal plasma, placenta, fetal brain, fetal carcass, and amniotic fluid was described, developing an adequate pharmacokinetic model. Maternal plasma levels of thiopental fell rapidly after injection, distributing into tissues (half-life of distribution phase averaged 3 min). Thiopental crossed the placenta and entered the fetal body (brain included) and amniotic fluid. Peak levels were seen within 10 min of injection and declined in all tissues parallel to maternal plasma (rate constant range 0.012-0.017 min-1). The concentrations of drug in the fetal unit were smaller than in the central compartment and maternal plasma. However, the absolute transfer ratios (calculated using the pharmacokinetic parameters obtained from the model) and the relative exposure ratios (as the ratio of the area under the unbound concentration-time curve in tissue to that in maternal plasma) suggested that fetuses were exposed to a potentially efficacious level of the drug. The model formulated to describe the tissue distribution of thiopental may offer a useful approach for analysis of the kinetic profile of other compounds administered during pregnancy or at delivery in rats and other species.

Drug Tissue Distribution: Study Methods and Therapeutic Implications

“…Regarding the disadvantages of PET, it should be recalled that radioisotopes with a short half-life are used and this is a limitation for the duration of pharmacokinetic studies; namely, only about 90-120 minutes for 11 C , up to a few hours for 76 Br. Nevertheless, the main disadvantage of the technique undoubtedly comes from quantification of the total radioactivity of the drug, no distinction being made between the unaltered drug and metabolites and the free and protein-bound drug [7].…”

“…Thus, such tissues can be considered as subcompartments subject to direct drug transference from the central compartment according to a first-order constant rate, which is an element of the transfer rate constant between the central and peripheral compartments. It is very useful in studies of transfer through the placenta and of drug pharmacokinetics in both the mother and foetus [75,76]. A model based on this strategy includes a hypothetical effect compartment and is applied to the study of the pharmacological effect in time [77].…”