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Application of stable isotope labeled diphenhydramine to study the pharmacokinetics and metabolism of diphenhydramine in pregnant, non-pregnant, and fetal sheep Tonn, George Roger
Abstract
Diphenhydramine (DPHM), an antihistamine, has been used in pregnant women; however, information regarding its disposition in human pregnancy is lacking. Recently, detailed pharmacokinetic studies in pregnant sheep have demonstrated that DPHM readily crosses the ovine placenta, and is eliminated from the fetus by placental and non-placental pathways. The purpose of this study is to investigate the components of the fetal non-placental elimination (i.e., fetal renal and hepatic), and to compare these to the estimates obtained from adult sheep. Since stable isotope techniques were to be employed, synthesis of stable isotope labeled DPHM (i.e., [²H10]DPH0M) and its major metabolite diphenylmethoxyacetic acid (i.e., [²H10]DPM0A) was required. Next, gas chromatographic - mass spectrometric methods were developed to simultaneously measure either DPHM and [²H10]DPH0M, or DPMA and [²H10]DPM0A. The current study demonstrates that the measured fetal renal clearance of DPHM contributes only ~2% to the observed fetal non-placental clearance. Overall, the total non-placental clearance of DPHM measured by direct methods (i.e., pulmonary [Yoo, 1989] and renal) can account for ~10% of the non-placental clearance. Unlike adult sheep, where hepatic extraction of DPHM was ~93%, no significant extraction of DPHM by the fetal liver following umbilical venous administration was observed. Therefore, fetal hepatic elimination is not likely to account for the remainder of the fetal non-placental clearance. However, fetal hepatic in vitro metabolism of DPHM (to form N-demethyl DPHM and DPMA) suggests that the fetal liver is capable of DPHM biotransformation. Thus, the liver and possibly other organs may contribute at least a portion of the fetal non-placental clearance via DPHM biotransformation. It appears that only a small fraction of the fetal non-placental clearance of DPHM can be accounted for by fetal renal and pulmonary clearances. While the low renal clearance of intact DPHM is similar both in fetus and mother, large differences in the hepatic uptake and/or metabolism of DPHM were observed between mother and fetus. This suggests that the pathways for the non-placental elimination of DPHM differ in mother and fetus. Despite the advances made in this study, the components of the fetal non-placental clearance remains largely unknown, and requires further study.
Item Metadata
Title |
Application of stable isotope labeled diphenhydramine to study the pharmacokinetics and metabolism of diphenhydramine in pregnant, non-pregnant, and fetal sheep
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
1995
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Description |
Diphenhydramine (DPHM), an antihistamine, has been used in pregnant women;
however, information regarding its disposition in human pregnancy is lacking. Recently, detailed
pharmacokinetic studies in pregnant sheep have demonstrated that DPHM readily crosses the
ovine placenta, and is eliminated from the fetus by placental and non-placental pathways. The
purpose of this study is to investigate the components of the fetal non-placental elimination (i.e.,
fetal renal and hepatic), and to compare these to the estimates obtained from adult sheep. Since
stable isotope techniques were to be employed, synthesis of stable isotope labeled DPHM (i.e.,
[²H10]DPH0M) and its major metabolite diphenylmethoxyacetic acid (i.e., [²H10]DPM0A) was
required. Next, gas chromatographic - mass spectrometric methods were developed to
simultaneously measure either DPHM and [²H10]DPH0M, or DPMA and [²H10]DPM0A. The
current study demonstrates that the measured fetal renal clearance of DPHM contributes only
~2% to the observed fetal non-placental clearance. Overall, the total non-placental clearance of
DPHM measured by direct methods (i.e., pulmonary [Yoo, 1989] and renal) can account for
~10% of the non-placental clearance. Unlike adult sheep, where hepatic extraction of DPHM
was ~93%, no significant extraction of DPHM by the fetal liver following umbilical venous
administration was observed. Therefore, fetal hepatic elimination is not likely to account for the
remainder of the fetal non-placental clearance. However, fetal hepatic in vitro metabolism of
DPHM (to form N-demethyl DPHM and DPMA) suggests that the fetal liver is capable of
DPHM biotransformation. Thus, the liver and possibly other organs may contribute at least a
portion of the fetal non-placental clearance via DPHM biotransformation. It appears that only a
small fraction of the fetal non-placental clearance of DPHM can be accounted for by fetal renal and pulmonary clearances. While the low renal clearance of intact DPHM is similar both in fetus
and mother, large differences in the hepatic uptake and/or metabolism of DPHM were observed
between mother and fetus. This suggests that the pathways for the non-placental elimination of
DPHM differ in mother and fetus. Despite the advances made in this study, the components of
the fetal non-placental clearance remains largely unknown, and requires further study.
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Extent |
5149201 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-06-05
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0088856
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
1995-05
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Item Media
Item Citations and Data
Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.