Vol. 27, Issue 4, 463-470, April 1999

Comparative Formation, Distribution, and Elimination Kinetics of Diphenylmethoxyacetic Acid (a Diphenhydramine Metabolite) in Maternal and Fetal Sheep

Sanjeev Kumar,¹ K. Wayne Riggs, and Dan W. Rurak

Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences (S.K., K.W.R.) and British Columbia Research Institute of Children's and Women's Health, Department of Obstetrics and Gynecology, Faculty of Medicine (D.W.R.), The University of British Columbia, Vancouver, British Columbia, Canada

Deamination to diphenylmethoxyacetic acid (DPMA) is the major route of diphenhydramine (DPHM) clearance in many species. In this study, we assessed the contribution of this pathway to nonplacental DPHM elimination and disposition of DPMA in maternal and fetal sheep. Paired maternal-fetal experiments were conducted in five chronically catheterized pregnant sheep (124-140 days gestation) with an appropriate washout period in between. Both maternal and fetal dosing experiments involved administration of an i.v bolus of deuterium-labeled DPMA ([²H₁₀]-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 analyzed for DPMA, [²H₁₀]-DPMA, DPHM, and deuterium-labeled DPHM concentrations using gas chromatography-mass spectrometry. The preformed DPMA (or [²H₁₀]-DPMA) had a substantially lower clearance (maternal: 0.55 ± 0.18 versus 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 of DPMA (or [²H₁₀]-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 metabolized in fetal or maternal sheep. These findings are in contrast to other species (dog, rhesus monkey, human) where DPMA and its conjugates constitute ~40 to 60% of the total DPHM metabolites.