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Human Fetal Liver Metabolism of Oxycodone Is Mediated by CYP3A7

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  • Theme: Celebrating Women in the Pharmaceutical Sciences
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Abstract

Oxycodone is an opioid analgesic that is commonly prescribed to pregnant women to treat moderate-to-severe pain. It has been shown to cross the placenta and distribute to the fetus. Oxycodone is mainly metabolized by CYP3A4 in the adult liver. Since CYP3A7 is abundantly expressed in the fetal liver and has overlapping substrate specificity with CYP3A4, we hypothesized that the fetal liver may significantly limit fetal exposure to oxycodone. This study showed that oxycodone is metabolized by CYP3A7 to noroxycodone in fetal liver microsomes (FLMs). The measured CYP3A7 expression was 191–409 pmol/mg protein in 14 FLMs, and an intersystem extrapolation factor (ISEF) for CYP3A7 was 0.016–0.066 in the panel of fetal livers using 6β-OH-testosterone formation as the probe reaction. Noroxycodone formation in the fetal liver was predicted from formation rate by recombinant CYP3A7, CYP3A7 expression level and the established ISEF value with average fold error of 1.25. Based on the intrinsic clearance of oxycodone measured in FLM, the fetal hepatic clearance (CLh) at term was predicted to be 495 (range: 66.4–936) μL/min, a value that is > 99% lower than the predicted adult liver CLh. The predicted fetal hepatic extraction ratio was 0.0019 (range: 0.00003–0.0036). These results suggest that fetal liver metabolism does not quantitatively contribute to the total systemic clearance of oxycodone in pregnant women nor does it provide a barrier for limiting fetal exposure to oxycodone. Additionally, since CYP3A7 forms noroxycodone, an inactive metabolite, the metabolism in the fetal liver is unlikely to affect fetal opioid activity.

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Funding

The CYP3A7 protein was a gift from the Emily Scott laboratory, generated by Jinghan Liu and funded under NIH grant R01AI150494. This work was supported by the NIH NCATS training grant TL1 TR002318, an NIH grant P01 DA032507, and the Elmer M. Plein Endowed Research Fund.

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  1. Department of Pharmaceutics, University of Washington, Seattle, Washington, USA

    Sara Shum & Nina Isoherranen

  2. University of Washington, Health Science Building Room H-272M, Box 357610, Seattle, Washington, USA

    Nina Isoherranen

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  1. Sara Shum
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Correspondence to Nina Isoherranen.

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Shum, S., Isoherranen, N. Human Fetal Liver Metabolism of Oxycodone Is Mediated by CYP3A7. AAPS J 23, 24 (2021). https://doi.org/10.1208/s12248-020-00537-x

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