Comparative formation, distribution, and elimination kinetics of diphenylmethoxyacetic acid (a diphenhydramine metabolite) in maternal and fetal sheep

Deamination to diphenylmethoxyacetic acid (DPMA) is the major route of diph enhydramine (DPHM) clearance in many species. In this study, we assessed th e contribution of this pathway to non-placental DPHM elimination and dispos ition of DPMA in maternal and fetal sheep. Paired maternal-fetal experiment s were conducted in five chronically catheterized pregnant sheep (124-140 d ays gestation) with an appropriate washout period in between. Both maternal and fetal dosing experiments involved administration of an i.v bolus of de uterium-labeled DPMA ([H-2(10)]-DPMA) combined with a 6-h infusion of DPHM (or a bolus of unlabeled DPMA with an infusion of deuterium-labeled DPHM). Maternal and fetal arterial plasma and urine samples were collected and ana lyzed for DPMA, [H-2(10)]-DPMA, DPHM, and deuterium-labeled DPHM concentrat ions using gas chromatography-mass spectrometry. The preformed DPMA (or [H- 2(10)]-DPMA) had a substantially lower clearance (maternal: 0.55 +/- 0.18 v ersus 40.9 +/- 14.0 ml/min/kg; fetal: 0.37 +/- 0.11 versus 285.6 +/- 122.2 ml/min/kg) and steady-state volume of distribution (Vd(ss), maternal: 0.10 +/- 0.02 versus 2.1 +/- 1.1 l/kg; fetal: 0.40 +/- 0.06 versus 13.1 +/- 3.1 l/kg) as compared with the parent drug. The contribution of DPMA formation to maternal and fetal DPHM nonplacental clearance in vivo was 1.78 +/- 2.12 % and 0.87 +/- 0.56%, respectively, indicating that DPMA formation is not a major route of DPHM clearance in fetal or maternal sheep. The recoveries o f DPMA (or [H-2(10)]-DPMA) in maternal urine were 88.0 +/- 6.5 and 92.1 +/- 7.4% of the administered dose during maternal and fetal dosing experiments , respectively. Thus, this metabolite does not appear to be secondarily met abolized in fetal or maternal sheep. These findings are in contrast to othe r species (dog, rhesus monkey, human) where DPMA and its conjugates constit ute similar to 40 to 60% of the total DPHM metabolites.