The ontogeny of P-glycoprotein in the developing human blood–brain barrier: implication for opioid toxicity in neonates

Abstract

Background:Neonates have been shown to have a heightened sensitivity to the central depressive effects of opioids compared to older infants and adults. The limited development of P-glycoprotein (P-gp) may limit the ability of the neonate to efflux morphine from the brain back to the systemic circulation. The objective of the study was to determine the ontogeny of P-gp in the human brain. Methods: Postmortem cortex samples from gestational age (GA) 20-26 wk, GA 36-40 wk, postnatal age (PNA) 0-3 mo, PNA 3-6 mo, and adults were immunostained for P-gp. results: The intensity of P-gp staining in adults was significantly higher compared to at GA 20-26 wk (P < 0.05), GA 36-40 wk (P < 0.05), and PNA 0-3 mo (P < 0.05). P-gp intensity at GA 20-26 wk (P < 0.05), GA 36-40 wk (P < 0.05), and PNA 0-3 mo (P < 0.05) was significantly lower compared to at PNA 3-6 mo. conclusion: P-gp expression in the brain is limited at birth, increases with postnatal maturation, and reaches adult levels at ~3-6 mo of age. Given the immaturity of blood-brain barrier (BBB) P-gp after birth, morphine may concentrate in the brain. This provides mechanistic support to life threatening opioid toxicity seen with maternal codeine use during breastfeeding.

Penetration of Treosulfan and its Active Monoepoxide Transformation Product into Central Nervous System of Juvenile and Young Adult Rats

“…Nevertheless, in one pediatric study (n = 70, including 46 infants), seizures occurred in four infants aged #4 months (Slatter et al, 2011). In such young children, organization of the neurovascular unit and expression of ABCB1 in the brain capillary endothelium is expected to be diminished in relation to those above 1 year of age, similar to when comparing the JR to the YAR used in our study (Gazzin et al, 2008;Ose et al, 2008;Saunders et al, 2012;Semple et al, 2013;Ghersi-Egea, 2013, 2015;Lam et al, 2015). One may hypothesize that the seizure appearance in those youngest patients could be related, at least in part, from the higher brain penetration of TREO and/or S,S-EBDM.…”

Question 1: Is it safe to use ivermectin in children less than five years of age and weighing less than 15 kg?

“…This was explained by a deficiency in p-glycoprotein 47. These effects have not been shown in humans; studies exploring p-glycoprotein levels in the developing human brain suggest the protein is present from an early gestation and levels increase with postnatal age, reaching adult levels by 3–6 months of age 48. Recent studies have also challenged the long-standing belief that the blood–brain barrier is ‘immature’, ‘leaky’ or ‘incomplete’ in newborns and young infants; these studies indicate that there is significant functional capacity early in brain development 49–51…”

Ivermectin to reduce malaria transmission I. Pharmacokinetic and pharmacodynamic considerations regarding efficacy and safety

“…P-gp expression at birth is quite low and reaches adult levels only after 6 months. This plays a large role in the susceptibility to central nervous effects from opioids [30] and possibly also for other P-gp substrates such as ivermectin. No controlled trials of ivermectin pharmacokinetics and safety have been performed in neonates and infants.…”