Abstract
The objective of this study was to examine the interrelationships between maternal and fetal plasma drug protein binding, umbilical blood flow (Qum), gestational age (GA), and maternal-fetal diphenhydramine (DPHM) clearances in chronically instrumented pregnant sheep. Maternal and fetal DPHM placental (CLmf and CLfm, respectively) and nonplacental (CLmo and CLfo, respectively) clearances and steady-state plasma protein binding were determined in 18 pregnant sheep at 124 to 140 days' gestation (term, ∼145 days). The data demonstrated a highly significant fall of ∼66% in CLfm and a decreasing trend in CLfo (∼47%) over the GA range studied. However, no such relationships existed between GA and CLmf or CLmo. Concomitant with this was a decrease in fetal DPHM plasma unbound fraction with GA, with no such change being evident in the mother. Both CLmo and CLfo were related to the respective DPHM plasma unbound fraction. A strong relationship also existed between fetal plasma unbound fraction and CLfm. Thus, the decrease in fetal unbound fraction of DPHM during gestation could contribute to the fall in CLfm, and possibly CLfo. However, over the GA range studied, fetal DPHM free fraction decreased by ∼47%, whereas CLfm fell by ∼66%. Because fetal unbound fraction and CLfm are linearly related, the GA-associated fall in unbound fraction appears to be insufficient to account for the entire decline in CLfm. In separate studies in pregnant sheep, we observed a ∼40% fall in weight-normalized Qum between 125 and 137 days' gestation. Because CLfm for DPHM is similar to that of flow-limited compounds (e.g., ethanol, antipyrine), this decrease in Qummay also contribute to the GA-related fall in CLfm.
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 West 28th Ave., Vancouver, British Columbia, Canada V5Z 4H4. E-mail:drurak{at}cw.bc.ca
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This study was supported by funding from the Medical Research Council of Canada. 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. A portion of this work was presented at the Association of American Pharmaceutical Scientists' 11th Annual Meeting and Exposition, Boston, and is presented in abstract form (Pharmaceut Res14:S330, 1997).
- Abbreviations used are::
- GA
- gestational age
- CLmf
- maternal-to-fetal placental clearance
- DPHM
- diphenhydramine
- [2H10]DPHM
- deuterium-labeled diphenhydramine
- CLmm
- maternal total body clearance
- CLff
- fetal total body clearance
- CLfm
- fetal-to-maternal placental clearance
- CLmo
- maternal nonplacental clearance
- CLfo
- fetal nonplacental clearance
- Cm
- maternal plasma steady-state diphenhydramine concentration after maternal administration
- Cf
- fetal plasma steady-state diphenhydramine concentration after maternal administration
- Cm′
- maternal plasma steady-state diphenhydramine (or deuterium-labeled diphenhydramine) concentration after fetal administration
- Cf′
- fetal plasma steady-state diphenhydramine (or deuterium-labeled diphenhydramine) concentration after fetal administration
- M-UF
- maternal steady-state plasma unbound fraction of the drug
- F-UF
- fetal steady-state plasma unbound fraction of the drug
- CLuint
- intrinsic clearance of the unbound drug
- QH
- hepatic blood flow
- Qum
- umbilical blood flow
- Received July 16, 1999.
- Accepted November 1, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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