Estimation of Transplacental and Nonplacental Diphenhydramine Clearances in the Fetal Lamb: The Impact of Fetal First-Pass Hepatic Drug Uptake1

  1. Sanjeev Kumar2,1,
  2. George R. Tonn3,1,
  3. Eddie Kwan2,
  4. Caroline Hall2,
  5. K. Wayne Riggs1,
  6. James E. Axelson1 and
  7. Dan W. Rurak4,2
  1. 1Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences (S.K., G.R.T., K.W.R., J.E.A.), and 2Department of Obstetrics and Gynecology, Faculty of Medicine (E.K., C.H., D.W.R.), University of British Columbia, Vancouver, B.C., Canada

    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

    • 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.

    • ↵1 This project was supported by Medical Research Council of Canada Program Grant PG-11120.

    • ↵2 S.K. is the recipient of a University of British Columbia Graduate Fellowship.

    • ↵3 G.R.T. was supported by a Medical Research Council of Canada Studentship.

    • ↵4 D.W.R. is the recipient of an Investigatorship award from the British Columbia Children’s Hospital Foundation.

    • ↵5 J.D. Gordon, K.W. Riggs, F.S. Abbott and D.W. Rurak, unpublished data.

    • ↵6 S. Kumar, G.R. Tonn, J.E. Axelson, D.W. Rurak and F.S. Abbott, unpublished observations.

    • ↵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.
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    1. JPET August 1, 1997 vol. 282 no. 2 617-632
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