A Literature Review of Changes in Phase II Drug-Metabolizing Enzyme and Drug Transporter Expression during Pregnancy

Gong, Christine; Bertagnolli, Lynn N.; Boulton, David W.; Coppola, Paola

doi:10.3390/pharmaceutics15112624

Cited by 4 publications

(6 citation statements)

References 100 publications

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“…The impact of physicochemical properties becomes more complex as physiological changes happen during the gestational period [ 108 , 109 ]. Protein binding alterations may be triggered during gestation as far as albumin and alpha1-acid glycoprotein concentrations in both maternal and cord blood are concerned [ 110 , 111 ]. Maternal serum albumin binding appears to decrease, which may lead to an increase in the free proportion of xenobiotics and, thereupon, to elevated placental transfer by passive diffusion [ 110 , 111 ].…”

Section: Resultsmentioning

confidence: 99%

“…Protein binding alterations may be triggered during gestation as far as albumin and alpha1-acid glycoprotein concentrations in both maternal and cord blood are concerned [ 110 , 111 ]. Maternal serum albumin binding appears to decrease, which may lead to an increase in the free proportion of xenobiotics and, thereupon, to elevated placental transfer by passive diffusion [ 110 , 111 ]. The ratio of albumin concentrations between maternal and fetal serum varies throughout the gestational period, potentially influencing the equilibrium of xenobiotics between these circulations.…”

Section: Resultsmentioning

confidence: 99%

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Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Kotta-Loizou,

Pritsa,

Antasouras

et al. 2024

Diseases

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Background: The placenta exerts a crucial role in fetus growth and development during gestation, protecting the fetus from maternal drugs and chemical exposure. However, diverse drugs and chemicals (xenobiotics) can penetrate the maternal placental barrier, leading to deleterious, adverse effects concerning fetus health. Moreover, placental enzymes can metabolize drugs and chemicals into more toxic compounds for the fetus. Thus, evaluating the molecular mechanisms through which drugs and chemicals transfer and undergo metabolism across the placental barrier is of vital importance. In this aspect, this comprehensive literature review aims to provide a holistic approach by critically summarizing and scrutinizing the potential molecular processes and mechanisms governing drugs and chemical transfer and metabolism across the placental barrier, which may lead to fetotoxicity effects, as well as analyzing the currently available experimental methodologies used to assess xenobiotics placental transfer and metabolism. Methods: A comprehensive and in-depth literature review was conducted in the most accurate scientific databases such as PubMed, Scopus, and Web of Science by using relevant and effective keywords related to xenobiotic placental transfer and metabolism, retrieving 8830 published articles until 5 February 2024. After applying several strict exclusion and inclusion criteria, a final number of 148 relevant published articles were included. Results: During pregnancy, several drugs and chemicals can be transferred from the mother to the fetus across the placental barrier by either passive diffusion or through placental transporters, resulting in fetus exposure and potential fetotoxicity effects. Some drugs and chemicals also appear to be metabolized across the placental barrier, leading to more toxic products for both the mother and the fetus. At present, there is increasing research development of diverse experimental methodologies to determine the potential molecular processes and mechanisms of drug and chemical placental transfer and metabolism. All the currently available methodologies have specific strengths and limitations, highlighting the strong demand to utilize an efficient combination of them to obtain reliable evidence concerning drug and chemical transfer and metabolism across the placental barrier. To derive the most consistent and safe evidence, in vitro studies, ex vivo perfusion methods, and in vivo animal and human studies can be applied together with the final aim to minimize potential fetotoxicity effects. Conclusions: Research is being increasingly carried out to obtain an accurate and safe evaluation of drug and chemical transport and metabolism across the placental barrier, applying a combination of advanced techniques to avoid potential fetotoxic effects. The improvement of the currently available techniques and the development of novel experimental protocols and methodologies are of major importance to protect both the mother and the fetus from xenobiotic exposure, as well as to minimize potential fetotoxicity effects.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Kotta-Loizou,

Pritsa,

Antasouras

et al. 2024

Diseases

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“…The study confirmed that metformin oral clearance was increased in nondiabetic pregnant women with PCOS compared with nonpregnant healthy volunteers or diabetic patients, which resulted in lower plasma metformin concentrations. These results are presumably determined by physiological changes during pregnancy, such as increased renal plasma flow ( 21 ) and possibly enhanced renal expression or function of organic cation transporter 2 ( 22 ), as factors contributing to the increased rate of metformin clearance. As a lower dose is effective for the treatment of prediabetes ( 19 ), the question arises whether it is necessary to adjust the dose in pregnant women with PCOS, bearing in mind that they have a faster elimination of the drug.…”

Section: Discussionmentioning

confidence: 99%

Factors contributing to variability in metformin concentration in polycystic ovary syndrome

Nikolić,

Stefanović,

Mitić

et al. 2024

Croat Med J

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“…Recent studies using buprenorphine and lamotrigine demonstrated that the activities of both phase one and phase two metabolic enzymes are affected by pregnancy, impacting maternal and fetal exposure to these drugs [ 50 , 51 ]. However, the changes in expression levels for phase two enzymes during pregnancy have not been characterized quantitatively yet [ 14 ]. As scientific knowledge evolves, further modeling studies will be performed to evaluate the ability of the pregnancy PBPK model to predict the changes in phase two metabolism in pregnancy.…”

Section: Discussionmentioning

confidence: 99%

“…However, Gong et al reviewed the effect of gestational age and hormonal regulation on the expression of phase two enzymes in pregnant woman and the placenta. As part of this review, they identified the current knowledge gaps in phase two enzyme localization, expression, and regulation during pregnancy [ 14 ]. Due to this knowledge gap, predicting the PK in pregnant patients for APIs cleared by phase two metabolic enzymes remains a challenge.…”

Section: Introductionmentioning

confidence: 99%

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Metabolism in Pregnant Subjects and Fetuses

Le Merdy,

Szeto,

Perrier

et al. 2024

Pharmaceutics

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This study aimed to develop a physiologically based pharmacokinetic (PBPK) model that simulates metabolically cleared compounds’ pharmacokinetics (PK) in pregnant subjects and fetuses. This model accounts for the differences in tissue sizes, blood flow rates, enzyme expression levels, plasma protein binding, and other physiological factors affecting the drugs’ PK in both the pregnant woman and the fetus. The PBPKPlus™ module in GastroPlus® was used to model the PK of metoprolol, midazolam, and metronidazole for both non-pregnant and pregnant groups. For each of the three compounds, the model was first developed and validated against PK data in healthy non-pregnant volunteers and then applied to predict the PK in the pregnant groups. The model accurately described the PK in both the non-pregnant and pregnant groups and explained well the differences in the plasma concentration due to pregnancy. When available, the fetal plasma concentration, placenta, and fetal tissue concentrations were also predicted reasonably well at different stages of pregnancy. The work described the use of a PBPK approach for drug development and demonstrates the ability to predict differences in PK in pregnant subjects and fetal exposure for metabolically cleared compounds.

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A Literature Review of Changes in Phase II Drug-Metabolizing Enzyme and Drug Transporter Expression during Pregnancy

Cited by 4 publications

References 100 publications

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Fetus Exposure to Drugs and Chemicals: A Holistic Overview on the Assessment of Their Transport and Metabolism across the Human Placental Barrier

Factors contributing to variability in metformin concentration in polycystic ovary syndrome

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Metabolism in Pregnant Subjects and Fetuses

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