In vitro, in vivo and in silico models of drug distribution into the brain

Summerfield, Scott; Dong, Kelly

doi:10.1007/s10928-013-9303-7

Cited by 25 publications

(26 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…P‐gp is expressed on the luminal membrane of the BBB and functions as the efflux transporter for pumping out lipophilic substrates that freely diffuse to endothelial cells. An in situ brain perfusion technique in rodents offers an ideal validation tool for assessing the in vitro BBB studies . Therefore, to confirm the influence of P‐gp on the amantadine transport at the luminal side of the BBB, the brain uptake of [ 3 H]amantadine was determined in the presence of a P‐gp inhibitor using an in situ brain perfusion technique in mice (Table ).…”

Section: Discussionmentioning

confidence: 99%

Possible involvement of cationic‐drug sensitive transport systems in the blood‐to‐brain influx and brain‐to‐blood efflux of amantadine across the blood–brain barrier

Suzuki

Fukami

Tomono

2014

Biopharm & Drug Disp

View full text Add to dashboard Cite

The purpose of this study was to characterize the brain-to-blood efflux transport of amantadine across the blood-brain barrier (BBB). The apparent in vivo efflux rate constant for [(3) H]amantadine from the rat brain (keff ) was found to be 1.53 × 10(-2) min(-1) after intracerebral microinjection using the brain efflux index method. The efflux of [(3) H]amantadine was inhibited by 1-methyl-4-phenylpyridinium (MPP(+) ), a cationic neurotoxin, suggesting that amantadine transport from the brain to the blood across the BBB potentially involves the rat plasma membrane monoamine transporter (rPMAT). On the other hand, other selected substrates for organic cation transporters (OCTs) and organic anion transporters (OATs), as well as inhibitors of P-glycoprotein (P-gp), did not affect the efflux transport of [(3) H]amantadine. In addition, in vitro studies using an immortalized rat brain endothelial cell line (GPNT) showed that the uptake and retention of [(3) H]amantadine by the cells was not changed by the addition of cyclosporin, which is an inhibitor of P-gp. However, cyclosporin affected the uptake and retention of rhodamine123. Finally, the initial brain uptake of [(3) H]amantadine was determined using an in situ mouse brain perfusion technique. Notably, the brain uptake clearance for [(3) H]amantadine was significantly decreased with the co-perfusion of quinidine or verapamil, which are cationic P-gp inhibitors, while MPP(+) did not have a significant effect. It is thus concluded that while P-gp is not involved, it is possible that rPMAT and the cationic drug-sensitive transport system participate in the brain-to-blood efflux and the blood-to-brain influx of amantadine across the BBB, respectively.

show abstract

Section: Discussionmentioning

confidence: 99%

Possible involvement of cationic‐drug sensitive transport systems in the blood‐to‐brain influx and brain‐to‐blood efflux of amantadine across the blood–brain barrier

Suzuki

Fukami

Tomono

2014

Biopharm & Drug Disp

View full text Add to dashboard Cite

show abstract

“…Methods to predict drug concentrations in the brain and associated limitations (adapted from Ball et al [42], Summerfield and Dong [78] and Pelkonen et al [79]). BBB, blood-brain barrier the human population [81].…”

Section: Figurementioning

confidence: 99%

Treating disorders of the neonatal central nervous system: pharmacokinetic and pharmacodynamic considerations with a focus on antiepileptics

Donovan

Boylan

Murray

et al. 2015

Brit J Clinical Pharma

View full text Add to dashboard Cite

A major consideration in the treatment of neonatal disorders is that the selected drug, dose and dosage frequency is safe, effective and appropriate for the intended patient population. Thus, a thorough knowledge of the pharmacokinetics and pharmacodynamics of the chosen drug within the patient population is essential. In paediatric and neonatal populations two additional challenges can often complicate drug treatment -the inherently greater physiological variability, and a lack of robust clinical evidence of therapeutic range. There has traditionally been an overreliance in paediatric medicine on extrapolating doses from adult values by adjusting for bodyweight or body surface area, but many other sources of variability exist which complicate the choice of dose in neonates. The lack of reliable drug dosage data in neonates has been highlighted by regulatory authorities, as only~50% of the most commonly used paediatric medicines have been examined in a paediatric population. Moreover, there is a paucity of information on the pharmacokinetic parameters which affect drug concentrations in different body tissues, and pharmacodynamic responses to drugs in the neonate. Thus, in the present review, we draw attention to the main pharmacokinetic factors that influence the unbound brain concentration of neuroactive drugs. Moreover, the pharmacodynamic differences between neonates and adults that affect the activity of centrally-acting therapeutic agents are briefly examined, with a particular emphasis on antiepileptic drugs. Neonatal drug treatmentsSafe, effective dosing regimens have not been elucidated for the majority of neonatal drug treatments, with up to 90% of critically ill infants receiving unlicensed (drugs which do not hold a marketing authorization) or off-label (therapeutic agents that are being used outside of the terms of their licence) drugs [1,2]. It is difficult for clinicians to choose a safe, effective dose for unlicensed therapeutic agents and off-label drugs as the doses of these drugs are often decided based on previous experience rather than clinical trial data [3,4]. The choice of dose is further complicated by the greater degree of pharmacokinetic and pharmacodynamic variability in neonates [5]. The central nervous system (CNS) undergoes significant changes as the neonate matures, culminating in major variability in neuroactive drug disposition and action [6]. However, robust clinical data on the pharmacokinetics and pharmacodynamics of centrally acting drugs in both term and preterm neonates is often sparse, which is a challenge when treating disorders of the neonatal CNS [7]. The key aims of the current review are to highlight the main British Journal of Clinical Pharmacology

show abstract

“…Some of the descriptors can be calculated using chemoinformatic approaches, [215][216][217] but the majority of the properties have to be experimentally measured in an array of biological profiling assays. The activities involved in characterizing compounds are organized into a screening cascade, which is then used to test and filter up to several thousand unique compounds to arrive ultimately at a clinical candidate.…”

Section: Screening Cascade For the Identification Of Optimized Smn2 Mmentioning

confidence: 99%

Assays for the Identification and Prioritization of Drug Candidates for Spinal Muscular Atrophy

Cherry

Kobayashi

Lynes

et al. 2014

ASSAY and Drug Development Technologies

View full text Add to dashboard Cite

In vitro, in vivo and in silico models of drug distribution into the brain

Cited by 25 publications

References 89 publications

Possible involvement of cationic‐drug sensitive transport systems in the blood‐to‐brain influx and brain‐to‐blood efflux of amantadine across the blood–brain barrier

Possible involvement of cationic‐drug sensitive transport systems in the blood‐to‐brain influx and brain‐to‐blood efflux of amantadine across the blood–brain barrier

Treating disorders of the neonatal central nervous system: pharmacokinetic and pharmacodynamic considerations with a focus on antiepileptics

Assays for the Identification and Prioritization of Drug Candidates for Spinal Muscular Atrophy

Contact Info

Product

Resources

About