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Application of stable isotope labeled diphenhydramine to study the pharmacokinetics and metabolism of diphenhydramine in pregnant, non-pregnant, and fetal sheep Tonn, George Roger


Diphenhydramine (DPHM), an antihistamine, has been used in pregnant women; however, information regarding its disposition in human pregnancy is lacking. Recently, detailed pharmacokinetic studies in pregnant sheep have demonstrated that DPHM readily crosses the ovine placenta, and is eliminated from the fetus by placental and non-placental pathways. The purpose of this study is to investigate the components of the fetal non-placental elimination (i.e., fetal renal and hepatic), and to compare these to the estimates obtained from adult sheep. Since stable isotope techniques were to be employed, synthesis of stable isotope labeled DPHM (i.e., [²H10]DPH0M) and its major metabolite diphenylmethoxyacetic acid (i.e., [²H10]DPM0A) was required. Next, gas chromatographic - mass spectrometric methods were developed to simultaneously measure either DPHM and [²H10]DPH0M, or DPMA and [²H10]DPM0A. The current study demonstrates that the measured fetal renal clearance of DPHM contributes only ~2% to the observed fetal non-placental clearance. Overall, the total non-placental clearance of DPHM measured by direct methods (i.e., pulmonary [Yoo, 1989] and renal) can account for ~10% of the non-placental clearance. Unlike adult sheep, where hepatic extraction of DPHM was ~93%, no significant extraction of DPHM by the fetal liver following umbilical venous administration was observed. Therefore, fetal hepatic elimination is not likely to account for the remainder of the fetal non-placental clearance. However, fetal hepatic in vitro metabolism of DPHM (to form N-demethyl DPHM and DPMA) suggests that the fetal liver is capable of DPHM biotransformation. Thus, the liver and possibly other organs may contribute at least a portion of the fetal non-placental clearance via DPHM biotransformation. It appears that only a small fraction of the fetal non-placental clearance of DPHM can be accounted for by fetal renal and pulmonary clearances. While the low renal clearance of intact DPHM is similar both in fetus and mother, large differences in the hepatic uptake and/or metabolism of DPHM were observed between mother and fetus. This suggests that the pathways for the non-placental elimination of DPHM differ in mother and fetus. Despite the advances made in this study, the components of the fetal non-placental clearance remains largely unknown, and requires further study.

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