Title : In vitro P-glycoprotein activity does not completely explain in vivo efficacy of novel centrally effective oxime acetylcholinesterase reactivators.

Pub. Date : 2019 Jul

PMID : 29722548






6 Functional Relationships(s)
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1 To determine if P-gp affinity screening could be used to reduce animal use, we measured in vitro oxime-stimulated ATPase activity to see if the in vivo reactivation efficacies related to the oximes" functions as P-gp substrates. Oximes ATP-binding cassette, subfamily B (MDR/TAP), member 1B Rattus norvegicus
2 To determine if P-gp affinity screening could be used to reduce animal use, we measured in vitro oxime-stimulated ATPase activity to see if the in vivo reactivation efficacies related to the oximes" functions as P-gp substrates. Oximes ATP-binding cassette, subfamily B (MDR/TAP), member 1B Rattus norvegicus
3 High efficacy oximes were expected to be poor P-gp substrates, thus remaining in the brain longer. Oximes ATP-binding cassette, subfamily B (MDR/TAP), member 1B Rattus norvegicus
4 The high efficacy oximes (24-35% brain AChE reactivation) were worse P-gp substrates than the low efficacy oximes (0-7% brain AChE reactivation). Oximes ATP-binding cassette, subfamily B (MDR/TAP), member 1B Rattus norvegicus
5 However, the oxime group with medium in vivo reactivation of 10-17% were even worse P-gp substrates than the high efficacy group so their reactivation ability was not reflected by P-gp export. Oximes ATP-binding cassette, subfamily B (MDR/TAP), member 1B Rattus norvegicus
6 The results suggest that in vitro P-gp ATPase activity can remove the low efficacy oximes from in vivo testing, but is not sufficient to differentiate between the top two tiers. Oximes ATP-binding cassette, subfamily B (MDR/TAP), member 1B Rattus norvegicus