How Does the Benzamide Antipsychotic Amisulpride get into the Brain?—An In Vitro Approach Comparing Amisulpride with Clozapine

Abstract

This study evaluated the disposition of the two atypical antipsychotics, amisulpride (AMS) and clozapine (CLZ), and its main metabolite N-desmethylclozapine (DCLZ), to their target structures in the central nervous system by applying an in vitro blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier based on monolayers of porcine brain microvessel endothelial cells (PMEC) or porcine choroid plexus epithelial cells (PCEC). Permeation studies through PMEC-and PCEC-monolayers were conducted for 60 min at drug concentrations of 1, 5, 10, and 30 mM applied to the donor compartment. PMEC were almost impermeable for AMS (permeation coefficient, Po1 Â 10 À7 cm/s) in the resorptive direction, whereas transport in the secretory direction was observed with a P ( 7 SD) of 5.2 7 3.6 Â 10 À6 cm/s. The resorptive P of CLZ and DCLZ were 2.3 7 1.2 Â 10 À4 and 9.6 7 5.0 Â 10 À5 cm/s, respectively. For the permeation across PCEC in the resorptive direction, a P of 1.7 7 2.5 Â 10 À6 cm/s was found for AMS and a P of 1.6 7 0.9 Â 10 À4 and 2.3 7 1.3 Â 10 À5 cm/s was calculated for CLZ and DCLZ, respectively. Both, CLZ and DCLZ, could easily pass both barriers with about a five-fold higher permeation rate of CLZ at the PCEC. The permeation of AMS across the BBB was restricted partly due to an efflux transport. It is thus suggested that AMS reaches its target structures via transport across the blood-CSF barrier.

Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine

“…24 Both studies concluded that ABCB1 genotyping should be considered to achieve optimal clozapine therapy. Several in vitro [28][29][30][31][32] and in vivo 20,33,34 studies reported that clozapine is not a substrate or a poor substrate of P-gp. 32 In contrast, clozapine metabolite N-desmethylclozapine has been shown to be a strong substrate to P-gp.…”

Effects of novel antipsychotics, amisulpiride and aripiprazole, on maternal behavior in rats

“…This long-lasting effect is probably due to the limited ability for amisulpiride to cross the blood-brain barrier and its negligible metabolism. Amisulpiride is one of the most hydrophilic antipsychotics and has difficulty permeating the blood-brain barrier (Hartter et al 2003), entering the CNS via a slower and less efficient mechanism through the choroid plexus. Its elimination from the body is mainly accomplished by renal clearance, which is a slow process because it is substantially reabsorbed from the distal portion of the nephron.…”

“…For amisulpiride, on day 6 postpartum, the first maternal behavior test commenced 0.5 h before drug injections, and the remaining tests were done at 3.5, 4.0, 5.0, and 7.0 h after the drug injections. The first drug test was at 3.5 h postinjection instead of the more standard 0.5 h postinjection because amisulpiride enters the brain via the choroid plexus, and this mechanism of entry is slower than other drugs (Hartter et al 2003). As mentioned above, our in vivo occupancy studies in rats show that even at 6 h postinjection, amisulpiride at 10, 30, and 100 mg/kg still gives rise to 60, 81, and 87% D 2 occupancies, respectively, a level of occupancies comparable to that observed in antipsychotictreated patients.…”

Improving the prediction of the brain disposition for orally administered drugs using BDDCS

“…The remaining seven drugs were false negatives since they were not BDDCS class 1. Saturable uptake processes have been implicated in the transport of amisulpride [125] and gabapentin [126,127] into the brain. Four other false negatives have been reported to be substrates for uptake transporters expressed in the brain [128]: rosuvastatin (OAT3, OATP1A2, OATP1B1, and OATP2B1) [129–131], zidovudine (OAT1, OAT2, OAT3, and OAT4) [132], trimethoprim (OCT2) [133], and chloroquine (OCT2) [133].…”