Abstract
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 (Vdss, 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.
Footnotes
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Send reprint requests to: Dr. Dan W. Rurak, B.C. Research Institute for Children’s and Women’s Health, 950 W. 28th Ave., Vancouver, BC, Canada V5Z 4H4. E-mail:dwr{at}wpog.childhosp.bc.ca
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↵1 Current address: Department of Drug Metabolism, P.O. Box 2000, RY80D-100, Merck Research Laboratories, Rahway, NJ 07065.
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These studies were supported by funding from the Medical Research Council of Canada. A part of this work was presented at the Association of American Pharmaceutical Scientists’ 10th Annual Meeting and Exposition, Seattle, WA and is abstracted in Pharmaceutical Research13:S425, 1996. S.K. was supported by a University of British Columbia Graduate Fellowship. D.W.R. is the recipient of an investigatorship award from the British Columbia Children’s Hospital Foundation.
- Abbreviations used are::
- DPHM
- diphenhydramine
- [2H10]-DPHM
- deuterium-labeled diphenhydramine
- DPMA
- diphenylmethoxyacetic acid
- [2H10]-DPMA
- deuterium-labeled diphenylmethoxyacetic acid
- AUC
- area under the plasma concentration versus time profile
- AUMC
- area under the first moment curve
- CLmm
- maternal total body clearance
- CLff
- fetal total body clearance
- CLmf
- maternal to fetal placental clearance
- CLfm
- fetal to maternal placental clearance
- CLmo
- maternal non-placental clearance
- CLfo
- fetal non-placental clearance
- CLtb
- total body clearance calculated as dose/AUC
- Cm
- maternal plasma steady-state DPHM concentration after maternal administration
- Cf
- fetal plasma steady-state DPHM concentration after maternal administration
- Cm’
- maternal plasma steady-state DPHM (or [2H10]-DPHM) concentration after fetal administration
- Cf’
- fetal plasma steady-state DPHM (or [2H10]-DPHM) concentration after fetal administration
- Cmax
- peak plasma concentration
- MA
- maternal femoral artery
- FA
- fetal femoral artery
- Fm
- fraction of total parent drug dose converted to metabolite
- Fm′
- formation clearance of the metabolite as a fraction of the non-placental clearance
- GA
- gestational age
- tmax
- time of peak plasma concentration
- Vdss
- steady-state volume of distribution
- MRT
- mean residence time
- Received July 13, 1998.
- Accepted December 18, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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