Sweeping physiological and biochemical changes occur during pregnancy, and the pharmacokinetics of many drugs are altered over the course of gestation. Small clinical studies suggest that the activity of many of the drug metabolizing enzymes is altered during pregnancy. For example, CYP1A2 activity decreases during pregnancy while CYP2D6 activity increases during pregnancy. As more than half of all women require prescription drugs at some point during pregnancy, it is vital to understand how pregnancy affects the drug metabolizing enzymes.
We propose that during pregnancy, circulating sex steroids, vitamins and cytokines act directly on hepatocytes to up- and down-regulate drug metabolizing enzymes through transcriptional mechanisms leading to altered enzyme synthesis. Furthermore, we propose that because pregnancy acts on enzyme expression, pharmacokinetic changes can be extrapolated from one substrate to another to predict pharmacokinetic changes during pregnancy.
In Chapter 2, we tested the hypothesis that pregnancy decreases CYPIA2 protein and mRNA expression during pregnancy using the rat as a representative animal model. We found that rat CYP1A2 activity, protein and mRNA decreased 50%, 29% and 27%, respectively, during late pregnancy. In Chapter 3, we evaluated the effects of the sex steroids, all-trans-retinoic acid and TGF-β1 on CYP1A2, CYP2C12 and CYP2D expression in female rat hepatocytes. We found that 17-β-estradiol, progesterone and testosterone induced CYP2C12 mRNA expression while all-trans-retinoic acid modulated CYP1A2 and CYP2D mRNA expression. In Chapter 4, we tested the hypothesis that the increase in the CYP2D6-mediated clearance of ( S)-fluoxetine during pregnancy could be quantitatively predicted using metoprolol data taken from the literature. We found that (S )-fluoxetine clearance increased 1.5-fold during late pregnancy although the change was not as great as predicted.
|School:||University of Washington|
|School Location:||United States -- Washington|
|Source:||DAI-B 71/10, Dissertation Abstracts International|
|Subjects:||Molecular biology, Pharmacology, Pharmacy sciences|
|Keywords:||Caffeine, Cytochrome P450, Drug metabolizing enzymes, Fluoxetine, Hepatic drug, Pregnancy|
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