Effect of Cytochrome P450 2D6 Genotype on Maternal Paroxetine Plasma Concentrations during Pregnancy

Ververs, F. F. T.; Voorbij, Heronimus A. M.; Zwarts, Petra; Belitser, Svetlana V.; Egberts, Toine C. G.; Visser, Gerard H.A.; Schobben, A. F. A. M.

doi:10.2165/11318050-000000000-00000

Cited by 84 publications

(83 citation statements)

References 38 publications

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“…Clonidine oral clearance increases 2-fold during pregnancy with no change in clonidine renal clearance, suggesting that the metabolic clearance presumably mediated by CYP2D6 (Buchanan et al, 2009;Claessens et al, 2010) was increased during pregnancy. Similarly, paroxetine clearance, likely mediated by CYP2D6, increased approximately 2-fold during gestation (Ververs et al, 2009). Taken together, these data unavoidably leave one to conclude that CYP2D6 function is enhanced during pregnancy, but raise questions of the true magnitude of change.…”

Section: Knowledge On Enzyme-specific Changes During Pregnancymentioning

confidence: 94%

Drug Metabolism and Transport During Pregnancy: How Does Drug Disposition Change during Pregnancy and What Are the Mechanisms that Cause Such Changes?

2013

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There is increasing evidence that pregnancy alters the function of drug-metabolizing enzymes and drug transporters in a gestationalstage and tissue-specific manner. In vivo probe studies have shown that the activity of several hepatic cytochrome P450 enzymes, such as CYP2D6 and CYP3A4, is increased during pregnancy, whereas the activity of others, such as CYP1A2, is decreased. The activity of some renal transporters, including organic cation transporter and P-glycoprotein, also appears to be increased during pregnancy. Although much has been learned, significant gaps still exist in our understanding of the spectrum of drug metabolism and transport genes affected, gestational age-dependent changes in the activity of encoded drug metabolizing and transporting processes, and the mechanisms of pregnancy-induced alterations. In this issue of Drug Metabolism and Disposition, a series of articles is presented that address the predictability, mechanisms, and magnitude of changes in drug metabolism and transport processes during pregnancy. The articles highlight state-of-the-art approaches to studying mechanisms of changes in drug disposition during pregnancy, and illustrate the use and integration of data from in vitro models, animal studies, and human clinical studies. The findings presented show the complex inter-relationships between multiple regulators of drug metabolism and transport genes, such as estrogens, progesterone, and growth hormone, and their effects on enzyme and transporter expression in different tissues. The studies provide the impetus for a mechanismand evidence-based approach to optimally managing drug therapies during pregnancy and improving treatment outcomes.

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Section: Knowledge On Enzyme-specific Changes During Pregnancymentioning

confidence: 94%

Drug Metabolism and Transport During Pregnancy: How Does Drug Disposition Change during Pregnancy and What Are the Mechanisms that Cause Such Changes?

2013

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“…Another prospective investigation found decreasing paroxetine levels from 16 to 40 weeks' gestation in UMs and EMs of CYP2D6. 32 In contrast, drug levels of the IMs and PMs increased with gestational age. In the same study, maternal depression scores also increased as pregnancy progressed in the EMs, suggesting a Gene × Environment (pregnancy) effect.…”

Section: Maternal Adaptations To Pregnancy and Its Impact On Ssri Andmentioning

confidence: 96%

“…In the same study, maternal depression scores also increased as pregnancy progressed in the EMs, suggesting a Gene × Environment (pregnancy) effect. 32 Given the differences in the CYPs' metabolic capacities and CYP inhibitory potencies of the drug themselves, further study of the links between an individual AD used in pregnancy and CYP genotypes is needed to characterize the alterations in the disposition of these drugs during pregnancy.…”

Section: Maternal Adaptations To Pregnancy and Its Impact On Ssri Andmentioning

confidence: 99%

Fetal Serotonin Reuptake Inhibitor Antidepressant Exposure: Maternal and Fetal Factors

2012

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Prenatal serotonin reuptake inhibitor exposure is common and neonatal outcomes vary greatly, often leading to confusion about whether to use or even continue antenatal use of these antidepressants. Importantly, some but not all infants are affected, which raises questions about how maternal drug metabolism contributes to fetal drug exposure. To address this key question, our paper reviews the role of key maternal, fetal, and placental pharmacokinetic, metabolic, and genetic factors that affect the extent of fetal drug exposure. Considering the role of these factors may further our understanding of variables that may assist in optimizing maternal psychopharmacotherapy during pregnancy and neonatal outcomes. W W WL'exposition prénatale à un inhibiteur du recaptage de la sérotonine est fréquente et les impacts néonataux varient grandement, ce qui provoque souvent la confusion lorsqu'il s'agit d'utiliser ou même de continuer l'usage prénatal de ces antidépresseurs. D'abord et avant tout, certains bébés, mais pas tous, sont affectés, ce qui soulève des questions sur la façon dont le métabolisme maternel des médicaments contribue à l'exposition foetale aux médicaments. Pour aborder cette importante question, notre article examine le rôle des principaux facteurs maternels, foetaux, pharmacocinétiques placentaires, métaboliques, et génétiques qui affectent la portée de l'exposition foetale aux médicaments. Examiner le rôle de ces facteurs approfondira notre compréhension des variables qui peuvent aider à optimiser la psychopharmacothérapie maternelle durant la grossesse et les résultats néonataux.consider the impact of physiological factors of the pregnancy itself and SRI-related pharmacological factors that influence maternal drug metabolism and, by extension, fetal exposure. Further, neonatal outcomes following in utero SRI exposure depends largely on the extent of fetal drug exposure, and thus understanding factors that affect fetal drug pharmacology also offers important clues to developmental risks associated with prenatal drug exposure. Our paper will review key maternal, placental, and fetal metabolic and genetic factors that influence SRI pharmacology and fetal drug exposure. Both SSRIs (for example, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) and SNRIs (for example, duloxetine and venlafaxine) are increasingly used to manage antenatal mood disturbances 8 and will be referred to as SRIs (meaning, SRI ADs). This review is offered as a way to further our understanding of variables that may account for the variations in maternal perinatal SRI pharmacology and neonatal outcomes, and thereby contribute to assessing the benefits and risks associated with SRI use in this setting. E ach year in North America, 15% to 20% of women experience mood disorders (for example, depression) during their pregnancy, leading to one-third of these women being treated with an SRI AD; however, up to 50% stop medication within the first 60 days of pregnancy.

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“…Similarly, the 24-hour DEX urinary metabolic ratio (UR: DEX/DXO) was significantly reduced throughout pregnancy in subjects phenotyped as EMs, with the greatest reduction (;1.9-fold PP:T 3 ) observed during T 3 (Tracy et al, 2005). In accordance with the increased CYP2D6 activity during pregnancy, paroxetine (PAR) plasma concentrations steadily decrease over the course of pregnancy in women genotyped as CYP2D6 EMs (Ververs et al, 2009). The most pronounced effect (73% reduction compared with postpartum) on PAR steady-state plasma concentrations is observed during T 3 .…”

Section: Introductionmentioning

confidence: 92%

“…In PMs, the predicted/observed values of mean SD and SS C max and C min were in the range of 1.0-1.3 (Supplemental Table 3). PAR exposure in pregnant women was predicted based on the study design described by Ververs et al (2009). In this study, subjects were genotyped, and steady-state (C ss,ave ) PAR plasma concentrations were examined in each of the three trimesters but not postpartum.…”

Section: Pbpk Prediction Of Pk Changes During Pregnancy 805mentioning

confidence: 99%

A Physiologically Based Pharmacokinetic Model to Predict Disposition of CYP2D6 and CYP1A2 Metabolized Drugs in Pregnant Women

Nallani

Zhao

et al. 2013

Drug Metab Dispos

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Conducting pharmacokinetic (PK) studies in pregnant women is challenging. Therefore, we asked if a physiologically based pharmacokinetic (PBPK) model could be used to evaluate different dosing regimens for pregnant women. We refined and verified our previously published pregnancy PBPK model by incorporating cytochrome P450 CYP1A2 suppression (based on caffeine PK) and CYP2D6 induction (based on metoprolol PK) into the model. This model accounts for gestational age-dependent changes in maternal physiology and hepatic CYP3A activity. For verification, the disposition of CYP1A2-metabolized drug theophylline (THEO) and CYP2D6-metabolized drugs paroxetine (PAR), dextromethorphan (DEX), and clonidine (CLO) during pregnancy was predicted. Our PBPK model successfully predicted THEO disposition during the third trimester (T 3 ). Predicted mean postpartum to third trimester (PP:T 3 ) ratios of THEO area under the curve (AUC), maximum plasma concentration, and minimum plasma concentration were 0.76, 0.95, and 0.66 versus observed values 0.75, 0.89, and 0.72, respectively. The predicted mean PAR steady-state plasma concentration (C ss ) ratio (PP:T 3 ) was 7.1 versus the observed value 3.7. Predicted mean DEX urinary ratio (UR) (PP:T 3 ) was 2.9 versus the observed value 1.9. Predicted mean CLO AUC ratio (PP:T 3 ) was 2.2 versus the observed value 1.7. Sensitivity analysis suggested that a 100% induction of CYP2D6 during T 3 was required to recover the observed PP:T 3 ratios of PAR C ss , DEX UR, and CLO AUC. Based on these data, it is prudent to conclude that the magnitude of hepatic CYP2D6 induction during T 3 ranges from 100 to 200%. Our PBPK model can predict the disposition of CYP1A2, 2D6, and 3A drugs during pregnancy.

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Effect of Cytochrome P450 2D6 Genotype on Maternal Paroxetine Plasma Concentrations during Pregnancy

Cited by 84 publications

References 38 publications

Drug Metabolism and Transport During Pregnancy: How Does Drug Disposition Change during Pregnancy and What Are the Mechanisms that Cause Such Changes?

Drug Metabolism and Transport During Pregnancy: How Does Drug Disposition Change during Pregnancy and What Are the Mechanisms that Cause Such Changes?

Fetal Serotonin Reuptake Inhibitor Antidepressant Exposure: Maternal and Fetal Factors

A Physiologically Based Pharmacokinetic Model to Predict Disposition of CYP2D6 and CYP1A2 Metabolized Drugs in Pregnant Women

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