Abstract
Previous estimates of maternal and fetal placental and nonplacental clearances in pregnant sheep using a two-compartment open model have revealed higher values of fetal placental clearance (CLfm) compared to the maternal placental clearance (CLmf) for most drugs. This includes the antihistamine diphenhydramine (DPHM), which also has the highest weight-corrected fetal nonplacental clearance (CLfo) among the drugs studied. This study was designed to determine the reasons for this CLfm − CLmf difference and to identify the sites of high CLfo for DPHM. DPHM and a stable isotope-labeled analog, [2H10]DPHM, were simultaneously infused to steady state to the mother and fetus, respectively, in five pregnant sheep. CLmf, CLfm, CLmo and CLfo averaged 50.3 ± 13.2, 214.4 ± 30.8, 36.6 ± 1.9 and 109.8 ± 22.3 ml/min−1/kg−1, respectively. By measuring diphenylmethoxyacetic acid and [2H10]diphenylmethoxyacetic acid levels in samples obtained from our previous study of fetal hepatic first-pass DPHM uptake, the hepatic first-pass extraction ratio of the drug from umbilical venous blood was estimated to be 0.44 ± 0.05. This can account for virtually all of CLfo. Fetal hepatic first-pass uptake of maternally derived DPHM in the paired infusion study reduces the fetal/maternal plasma DPHM concentration ratio and results in significant underestimation of CLmf. When the CLmf estimate is corrected for this factor and for maternal-fetal DPHM plasma protein binding differences, its value approaches CLfm. Fetal hepatic first-pass uptake may also be a factor in the underestimation of CLmf for most of the other drugs. Conversely, a lower value of CLmf compared with CLfm provides evidence for significant fetal hepatic uptake of these compounds.
Footnotes
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Send reprint requests to: Dr. Dan W. Rurak, B.C. Institute for Child and Family Health, 950 West 28th Avenue, Vancouver, B.C., Canada V5Z 4H4.
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↵1 This project was supported by Medical Research Council of Canada Program Grant PG-11120.
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↵2 S.K. is the recipient of a University of British Columbia Graduate Fellowship.
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↵3 G.R.T. was supported by a Medical Research Council of Canada Studentship.
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↵4 D.W.R. is the recipient of an Investigatorship award from the British Columbia Children’s Hospital Foundation.
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↵5 J.D. Gordon, K.W. Riggs, F.S. Abbott and D.W. Rurak, unpublished data.
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↵6 S. Kumar, G.R. Tonn, J.E. Axelson, D.W. Rurak and F.S. Abbott, unpublished observations.
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↵7 S. Kumar, F.S. Abbott, J.E. Axelson and D.W. Rurak, unpublished observations.
- Abbreviations:
- DPHM
- diphenhydramine
- [2H10]DPHM
- deuterium-labeled diphenhydramine
- DPMA
- diphenylmethoxyacetic acid
- [2H10]DPMA
- deuterium-labeled diphenylmethoxyacetic acid
- CLmm
- maternal total body clearance
- CLff
- fetal total body clearance
- CLmf
- maternal-to-fetal transplacental clearance
- CLfm
- fetal-to-maternal transplacental clearance
- CLmo
- maternal nonplacental clearance
- CLfo
- fetal nonplacental clearance
- AUC
- area under the plasma concentration-vs.-time curve
- MA
- maternal femoral artery
- MV
- maternal femoral vein
- FA
- fetal femoral artery
- UV
- umbilical vein
- TV
- fetal lateral tarsal vein
- CA
- fetal carotid artery
- Cmss
- maternal plasma steady-state DPHM concentration after maternal administration
- Cfss
- fetal plasma steady-state DPHM concentration after maternal administration
- Cmss′
- maternal plasma steady-state [2H10]DPHM concentration after fetal administration
- Cfss′
- fetal plasma steady-state [2H10]DPHM concentration after fetal administration
- Qum
- umbilical blood flow
- ER
- fetal hepatic extraction ratio for DPHM present in umbilical blood
- F
- fetal systemic availability for DPHM present in umbilical blood
- GFR
- glomerular filtration rate
- GC-MS
- gas chromatography-mass spectrometry
- LOQ
- limit of quantification
- Received July 22, 1996.
- Accepted April 8, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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