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Maternal-fetal disposition, fetal pharmacodynamics and comparative pharmacokinetics of diphenhydramine in pregnant and nonpregnant sheep Yoo, Sun Dong


A capillary GC/NPD assay method which provides improved sensitivity and selectivity for diphenhydramine is reported. The assay method involves single drug extraction and splitless sample injection. Standard curves are linear in the range of 2-320 ng/mL of diphenhydramine, which represents an amount of the drug from ~40 pg to 6.4 ng at the detector. This assay method was used in the subsequent studies of the maternal-fetal disposition and comparative pharmacokinetics of the drug in pregnant and nonpregnant sheep. Pharmacokinetics of the drug were characterized in the nonpregnant sheep after i.v. bolus injection of 25, 50, 100 and 200 mg doses on a crossover basis. The total body clearance and dose-normalized AUC remained unchanged over the dose range studied. There were, however, significant increases in the elimination half-life and volume of distribution after a 200 mg dose, as compared to those after 25 mg dose. The plasma free fraction of the drug (0.229) was independent of drug concentrations over the range of 10-2,000 ng/mL. The disposition of diphenhydramine in the maternal and fetal plasma, fetal tracheal and amniotic fluids was studied in the chronically catheterized maternal-fetal sheep following maternal i.v. bolus injection or maternal and fetal i.v. infusions. Following maternal i.v. bolus injection, the drug was rapidly transferred from th ewe to the fetus, resulting in significant fetal drug exposure (fetal/maternal AUC ratio, ~0.9). There was no significant difference in the pharmacokinetic parameters between the pregnant and nonpregnant ewes. Plasma free fraction of the drug in the pregnant sheep was not significantly different from that in the nonpregnant sheep, but was smaller than that in the fetus (0.141 vs. 0.277). The total body clearance in the fetus (472.7 mL/min) was smaller than in the mother (3426.1 mL/min). The transplacental clearance from fetus to mother (264.4 mL/min) was ~3 times higher than that from mother to fetus (82.4 mL/min). Maternal nonplacental clearance (3343.8 mL/min) accounted for ~98% of the maternal total body clearance, whereas fetal nonplacental clearance (208.4 mL/min) accounted for ~45% of the fetal total clearance. Therefore, in the ewe, the drug appeared to be eliminated mainly by nonplacental pathways. However, in the fetus, both placental and nonplacental pathways are important for drug elimination. Maternal drug infusions resulted in fetal CNS depressant effects, whereas fetal infusions resulted in stimulation; this difference could be attributed to the different fetal plasma drug concentrations achieved. Diphenhydramine accumulated both in the amniotic and fetal tracheal fluids. Following injection of diphenhydramine into the amniotic cavity, an average of 63% was eliminated by the mother, of which, ~47% was received from the fetus and the rest (16%) from the amniotic fluid via direct diffusion across the uterus. Also, ~37% of the total available drug was eliminated by the fetus, which is greater than that obtained after maternal i.v. bolus injection (~5%) or maternal infusion (~2%) but is comparable to that after fetal infusion (~45%). Diphenhydramine injected into the amniotic sac, therefore, appeared to be preferentially taken up by the fetus, resulting in much greater degree of fetal drug exposure than maternal exposure. The fetal pulmonary extraction ratio of the drug at steady-state averaged ~0.08 and the delivery of the drug to the lungs via the pulmonary circulation seemed to be sufficient to account for drug accumulation in the fetal tracheal fluid.

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