There is increasing evidence that pregnancy alters the function of drug-metabolizing enzymes and drug transporters in a gestational-stage and tissue-specific manner. this issue (Shuster et al., 2013). Some differences in individual Cyp2d mRNA expression were, however, observed between the two studies, highlighting the challenges of quantifying pregnancy-mediated changes in mice. Interestingly, in the microarray study of the changes in the hepatic and renal mRNA expression of genes related to drug disposition, including P450, UGT, YM201636 and sulfotransferase genes (Shuster et al., 2013), the authors report that increases in UGT mRNAs were not observed, despite the increase in lamotrigine (UGT1A4) metabolic clearance that occurs during human pregnancy. This issue of also shows that the expression of carboxylesterases is decreased during mouse pregnancy (Fortin et al., 2013). This is of interest as oseltamivir, a drug used to prevent influenza and H1N1 virus infection during pregnancy, is converted to its active entity oseltamivir carboxylate by carboxylesterases (primarily CES-1). During pregnancy, oseltamivir exposure and oral clearance were not altered compared with nonpregnant controls, suggesting carboxylesterase activity is unchanged during human pregnancy (Beigi et al., 2011). However, exposure to oseltamivir carboxylate was lower in pregnant than nonpregnant women. This is most likely due to an increase in the clearance of the metabolite, in YM201636 the absence of a change in parent drug AUC and a parallel oseltamivir clearance pathway. Better validation of the mouse model and understanding of the mechanisms of decreased carboxylesterase mRNA in the mouse will be helpful to determine the mechanisms of oseltamivir clearance changes in humans. With regard to drug transport in the pregnant mouse model, it was found that both renal Mdr1b (Yacovino et al., 2013) and Mdr1a (Shuster et al., 2013) expression were decreased during gestation, whereas digoxin renal clearance is increased in humans (Hebert et al., 2008). Similarly, renal Oct2 and Oct3 mRNA was reported to be unchanged in mice, and Oct1 mRNA was downregulated at day 7 of gestation and mildly (1.1-fold) upregulated on day 17 of pregnancy (Yacovino et al., 2013), despite the observed significant increase in metformin renal secretion in humans (Eyal et al., 2010). It is possible that the increase in metformin renal clearance during pregnancy is due to increased expression of MATE instead of OCT3, as MATE1 and MATE2 have been suggested to contribute to metformin renal clearance (Tanihara et al., 2007; Kusuhara et al., 2011). However, the mRNA of Mate1 was also consistently decreased in mouse kidney during gestation (Shuster et al., 2013; Yacovino et al., 2013). Of the renal transporters, only Mrp3 mRNA was increased during pregnancy. As such, a better validation of renal clearance changes in the mouse during pregnancy is needed. Overall, these available data show that any animal model used to study mechanisms of changes in drug disposition during pregnancy should be validated for the enzyme/transporter of interest YM201636 and shown to replicate the phenomenon of interest in humans. Although the data presented collectively provide a foundation for the mouse model as a system to evaluate YM201636 pregnancy-mediated changes in drug disposition, it is clear that we are still far from understanding the detailed mechanisms of how drug-metabolizing and transport activities are altered during pregnancy. An interesting aspect of the mouse data is that, for transporters Rabbit Polyclonal to Patched. that are expressed in multiple tissues such as the placenta, maternal kidney, and the liver and fetal tissues, the regulation of these enzymes during pregnancy appears to be tissue-specific. To gain an understanding of tissue-specific regulation, novel tools clearly need to be developed to allow extrapolation of mechanistic findings to specific tissues in vivo. Mechanistic Studies Using In Vitro Systems to Evaluate Regulation of Drug-Metabolizing Enzymes and Transporters during Pregnancy Potentially the most challenging aspect of studying drug disposition during pregnancy relates to establishing a clear link between regulatory control of drug-metabolizing enzymes and transporters by endogenous compounds in vitro and the changes in relevant cell exposure to these endogenous compounds during pregnancy. Just because a compound can elicit an increase or decrease in the expression of an enzyme or transporter in vitro does not necessarily mean that altered systemic or local concentrations of that molecule are responsible for changes in tissue drug metabolism and transport gene expression during pregnancy. For example, three studies in this issue of approach the.