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Drug disposition in the maternal-fetal unit : studies with diphenhydramine and valproic acid in pregnant sheep

University of British Columbia

Diphenhydramine (DPHM, a high clearance amine) and valproic acid (VPA, a low clearance carboxylic acid) disposition was examined in chronically-instrumented pregnant sheep during late gestation (after 120 d, term 145 d) in order to: i) identify the important pharmacokinetic factors determining fetal drug exposure, and ii) examine the in utero fetal drug metabolism capacity for these two compounds. Both drugs underwent rapid placental transfer after maternal dosing. Although the placental permeability for DPHM was higher, the steady-state fetal exposure relative to the mother was greater for VPA (70% vs. 20%). Significant fetal drug elimination capacity was detectable for both compounds, with DPHM having a much higher clearance. Moreover, there was significant (~44%) fetal hepatic first-pass uptake of the placentally transferred DPHM from the umbilical vein due to the unique geometrical position of the fetal liver. These factors were responsible for the observed lower fetal exposure to DPHM. Maternal and fetal placental and non-placental clearances of both drugs were highly dependent on their plasma protein binding. However, for DPHM, the importance of plasma protein binding in determining fetal drug exposure was overridden by the above more pronounced effect of the fetal liver. Metabolism to diphenylmethoxyacetic acid (DPMA), and DPHM-N-oxide renal excretion accounted for only 1-2% of the DPHM dose in maternal and fetal sheep, as opposed to 50-80% in the monkey, dog and human. Also, DPMA was not secondarily metabolized in sheep. Approximately 95% of the maternal VPA dose was eliminated via glucuronidation and renal excretion, with p-oxidation and cytochrome P-450 pathways accounting for the remainder. All these pathways appeared to be functional in the fetus; however, the low fetal VPA clearance could not be accurately measured. Studies conducted in 1 day old lambs revealed -18 fold lower weight-normalized VPA elimination capacity relative to the mother, and this led to a lower newborn VPA clearance and longer half-life, as observed in human newborns. The reduced newborn lamb VPA elimination was mainly attributable to underdeveloped glucuronidation and renal excretion ability; this, combined with a high p-oxidation capacity at birth, resulted in a larger fraction of the VPA dose (~20%) being metabolized via p-oxidation and cytochrome P-450 pathways in lambs.

Thesis/Dissertation

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2009-06-22

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http://hdl.handle.net/2429/9522

Pharmaceutical Sciences

University of British Columbia

UBCV

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