Mind the Gaps: Ontogeny of Human Brain P-gp and Its Impact on Drug Toxicity

Nicolas, Jean‐Marie; Lange, Elizabeth C. M. de

doi:10.1208/s12248-019-0340-z

Cited by 12 publications

(6 citation statements)

References 139 publications

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“…As this method only allows semi-quantitative analysis, we were able to describe developmental patterns, but not quantitative differences. Moreover, as discussed before, disease conditions, medication, delay between death and autopsy, and IHC methodology (e.g., methods of fixation) may have influenced the identified age-related variation (Brouwer et al 2015 ; Nicolas and de Lange 2019 ). Reports have indicated that especially inflammation and ischemia influence transporter expression in transporter protein and organ dependent fashion (Evers et al 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Developmental patterns in human blood–brain barrier and blood–cerebrospinal fluid barrier ABC drug transporter expression

Verscheijden

Hattem

Pertijs

et al. 2020

Histochem Cell Biol

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When drugs exert their effects in the brain, linear extrapolation of doses from adults could be harmful for children as the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) function is still immature. More specifically, age-related variation in membrane transporters may impact brain disposition. As human data on brain transporter expression is scarce, age dependent [gestational age (GA), postnatal age (PNA), and postmenstrual age (PMA)] variation in immunohistochemical localization and staining intensity of the ABC transporters P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins 1, 2, 4, and 5 (MRP1/2/4/5) was investigated. Post mortem brain cortical and ventricular tissue was derived from 23 fetuses (GA range 12.9-39 weeks), 17 neonates (GA range 24.6-41.3 weeks, PNA range 0.004-3.5 weeks), 8 children (PNA range 0.1-3 years), and 4 adults who died from a wide variety of underlying conditions. In brain cortical BBB, immunostaining increased with age for Pgp and BCRP, while in contrast, MRP1 and MRP2 staining intensity appeared higher in fetuses, neonates, and children, as compared to adults. BCSFB was positively stained for Pgp, MRP1, and MRP2 and appeared stable across age, while BCRP was not detected. MRP4 and MRP5 were not detected in BBB or BCSFB. In conclusion, human BBB and BCSFB ABC membrane transporters show brain location and transporter-specific maturation.

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Section: Discussionmentioning

confidence: 99%

Developmental patterns in human blood–brain barrier and blood–cerebrospinal fluid barrier ABC drug transporter expression

Verscheijden

Hattem

Pertijs

et al. 2020

Histochem Cell Biol

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“…Because the central nervous system (CNS) is an important site of action for many drugs, age‐related patterns in the expression of efflux transporters in the blood–brain and blood–CSF barriers may be of clinical importance. Given the limited availability of sufficient amount of human tissue to conduct quantitative proteomic investigations, the monitoring of radiolabelled compounds using positron emission tomography and the measurement of central pharmacodynamic responses have been proposed as potential means to characterize the ontogeny of P‐gp in the blood brain barrier 90 . However, there are considerable practical challenges to conducting positron emission tomography imaging studies in the paediatric population including requiring exposure to radiation and sedative drugs, which may be required to reduce the movement of paediatric subjects while obtaining measurements 91 .…”

Section: Distributionmentioning

confidence: 99%

Recent advances in the ontogeny of drug disposition

Chapron

Leeder

2021

Brit J Clinical Pharma

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Developmental changes that occur throughout childhood have long been known to impact drug disposition. However, pharmacokinetic studies in the paediatric population have historically been limited due to ethical concerns arising from incorporating children into clinical trials. As such, much of the early work in the field of developmental pharmacology was reliant on difficult‐to‐interpret in vitro and in vivo animal studies. Over the last 2 decades, our understanding of the mechanistic processes underlying age‐related changes in drug disposition has advanced considerably. Progress has largely been driven by technological advances in mass spectrometry‐based methods for quantifying proteins implicated in drug disposition, and in silico tools that leverage these data to predict age‐related changes in pharmacokinetics. This review summarizes our current understanding of the impact of childhood development on drug disposition, particularly focusing on research of the past 20 years, but also highlighting select examples of earlier foundational research. Equally important to the studies reviewed herein are the areas that we cannot currently describe due to the lack of research evidence; these gaps provide a map of drug disposition pathways for which developmental trends still need to be characterized.

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“…Morphine is a substrate of P-glycoprotein (Pgp)/ABCB1, which is highly expressed at the luminal side of the BBB. Differences in brain morphine disposition may explain the variability in efficacy as we and others found that BBB Pgp expression is immature in neonates and young infants [9][10][11][12]. Animal studies also point towards a developmental increase in brain Pgp activity and indicate that morphine brain concentrations increase by a factor of 1.7 in adult Pgp knocked out mice [13,14].…”

Section: Introductionmentioning

confidence: 65%

Physiologically based pharmacokinetic/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children

Verscheijden

Litjens²,

Koenderink

et al. 2021

PLoS Comput Biol

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Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. To assess the influence of these processes on morphine effectiveness, a multi-compartment brain physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) model was developed in R (Version 3.6.2). Active Pgp-mediated morphine transport was measured in MDCKII-Pgp cells grown on transwell filters and translated by an in vitro-in vivo extrapolation approach, which included developmental Pgp expression. Passive BBB permeability of morphine and its active metabolite morphine-6-glucuronide (M6G) and their pharmacodynamic parameters were derived from experiments reported in literature. Model simulations after single dose morphine were compared with measured and published concentrations of morphine and M6G in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF), as well as published drug responses in children (1 day– 16 years) and adults. Visual predictive checks indicated acceptable overlays between simulated and measured morphine and M6G concentration-time profiles and prediction errors were between 1 and -1. Incorporation of active Pgp-mediated BBB transport into the PB-PK/PD model resulted in a 1.3-fold reduced brain exposure in adults, indicating only a modest contribution on brain disposition. Analgesic effect-time profiles could be described reasonably well for older children and adults, but were largely underpredicted for neonates. In summary, an age-appropriate morphine PB-PK/PD model was developed for the prediction of brain pharmacokinetics and analgesic effects. In the neonatal population, pharmacodynamic characteristics, but not brain drug disposition, appear to be altered compared to adults and older children, which may explain the reported differences in analgesic effect.

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Mind the Gaps: Ontogeny of Human Brain P-gp and Its Impact on Drug Toxicity

Cited by 12 publications

References 139 publications

Developmental patterns in human blood–brain barrier and blood–cerebrospinal fluid barrier ABC drug transporter expression

Developmental patterns in human blood–brain barrier and blood–cerebrospinal fluid barrier ABC drug transporter expression

Recent advances in the ontogeny of drug disposition

Physiologically based pharmacokinetic/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children

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