Ontogeny of plasma proteins, albumin and binding of diazepam, cyclosporine, and deltamethrin

Considering Age Variation When Coining Drugs as High versus Low Hepatic Extraction Ratio

“…Although it is not relevant to the cases represented in this study, the ontogeny of plasma proteins can play a significant role in agerelated changes of the E H for highly bound, low-extraction drugs. As shown previously by several investigators, the concentration of plasma proteins increases with age whereas the unbound fraction of drugs in plasma and thus in blood decreases with age (McNamara and Alcorn, 2002;Johnson et al, 2006;Sethi et al, 2015).…”

“…(B) Relative values of serum albumin (Johnson et al, 2003(Johnson et al, , 2006Sethi et al, 2015), CYP3A4 abundance (of relevance to our study) (Salem et al, 2014) alongside age variation in serum alpha-acid glycoprotein (AAG) (Johnson et al, 2003(Johnson et al, , 2006, and abundance of CYP1A2 (Salem et al, 2014). The impact of the parameters shown in B will depend on the relative importance of the protein binding to each protein and the role of the specific enzyme to overall elimination.…”

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

“…It could be hypothesized that the higher CSF levels in neonates relate to immature brain Pgp. However, as for VCR, these data should be interpreted with caution since the role of P-gp in AmB distribution is still debated (64,65) and age-related changes in plasma protein binding may have also contributed to the higher AmB CSF concentrations in neonates (66). Moreover, it should be realized that CSF concentrations do not directly reflect brain extracellular fluid (ECF) concentrations.…”

Children in clinical trials: towards evidence-based pediatric pharmacotherapy using pharmacokinetic-pharmacodynamic modeling

“…Moreover, the drug-protein binding to albumin and α1-acid glycoprotein increases with increasing age, due to an increase in protein expression and binding capacity. This results in an decreased unbound drug fraction (25,26), although for most drugs changes in protein binding have no clinical consequence.…”