Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein

Abstract

The objective of this study was to assess the potential interactions of the drug transporter Pglycoprotein with attention-deficit/hyperactivity disorder (ADHD) therapeutic agents atomoxetine -and the individual isomers of methylphenidate, amphetamine, and modafinil utilizing established in vitro assay. An initial ATPase assay indicated that both d-and l-methylphenidate have weak affinity for P-glycoprotein. The intracellular accumulation of P-glycoprotein substrates doxorubicin and rhodamine123 in the P-glycoprotein overexpressing cell line LLC-PK1/MDR1 was determined to evaluate potential inhibitory effects on P-glycoprotein. The results demonstrated that all compounds, except both modafinil isomers, significantly increased doxorubicin and rhodamine123 accumulation in LLC-PK1/MDR1 cells at higher concentrations. To investigate the P-glycoprotein substrate properties, the intracellular concentrations of the tested compounds in LLC-PK1/MDR1 and P-glycoprotein negative LLC-PK1 cells were measured in the presence and absence of the Pglycoprotein inhibitor PSC833. The results indicate that the accumulation of d-methylphenidate in LLC-PK1 cells was 32.0% higher than in LLC-PK1/MDR1 cells. Additionally, coadministration of PSC833 leads to 52.9% and 45.6% increases in d-modafinil and l-modafinil accumulation, respectively, in LLC-PK1/MDR1 cells. Further studies demonstrated that l-modafinil transport across LLC-PK1/MDR1 cell monolayers in the basolateral-to-apical (B-A) direction was significantly higher than in the apical-to-basolateral (A-B) direction. PSC833 treatment significantly decreased the transport of l-modafinil in B-A direction. In conclusion, our results suggest that all tested agents with the exception of modafinil isomers are relatively weak P-glycoprotein inhibitors. Furthermore, P-glycoprotein may play a minor role in the transport of d-methylphenidate, dmodafinil, and l-modafinil.

Plasma Methylphenidate Levels in Youths With Attention Deficit Hyperactivity Disorder Treated With OROS Formulation

“…4,15 Previous studies reported that MPH was relatively free of pharmacokinetically drug interactions. 7,21 In line with these studies, because risperidone, sertraline, fluoxetine, and aripiprazole are metabolized primarily through cytochrome P450 enzymes 2D6, 3A4, and 2C19, 22,23 no drug effects (including risperidone, sertraline, fluoxetine, and aripiprazole) on the absolute and dose-related plasma levels of MPH have been found in this study. It can be considered that these drugs do not also interact in other ways as in way of hepatic metabolism.…”

An in vitro evaluation of guanfacine as a substrate for P-glycoprotein

“…Combined pharmacotherapy in child, adolescent, and adult psychiatric patients has recently become a growing practice 24–26. Because ADHD therapeutic agents are the most commonly used psychotropic drugs in children and adolescents and are often used in combination with other therapeutic agents on an acute or chronic basis, the potential for drug–drug interactions, at least in theory, is extremely high 27–29…”

“…Additionally, Wang et al reported that the antipsychotic risperidone and its active metabolite, 9-hydroxy-risperidone, are both P-gp substrates 31. Other psychotropic agents that have been documented as substrates of P-gp to some degree include ( R )-methadone, ( S )-methadone, olanzapine, d -modafinil, l -modafinil, and d- methylphenidate 29,32,33. Because P-gp is the most important efflux transporter at the blood–brain barrier, entry of these substrates into the central nervous system is greatly limited.…”

“…Because P-gp is the most important efflux transporter at the blood–brain barrier, entry of these substrates into the central nervous system is greatly limited. Furthermore, a number of psychotropic drugs have been found to be P-gp inhibitors, which may affect disposition of coadministered P-gp substrates 29,34,35…”

In vitro study methodologies to investigate genetic aspects and effects of drugs used in attention-deficit hyperactivity disorder

“…In a study in which HEK cells were transfected with four different DAT1 constructs (hDAT, DAT1 coding the region necessary and sufficient to produce a functional transporter protein; hDAT Zero, a construct containing the DAT1 coding region flanked by an ~800 bp fragment of the 3'-UTR upstream of the VNTR region; hDAT 9, a construct with the DAT1 coding region upstream of a full length 3'-UTR harbouring the 9-repeat VNTR; hDAT 10, a construct with the DAT1 coding region In studying the transport of drugs into the central nervous system (CNS), Zhu et al used the porcine kidney epithelial cell line LLC-PK1 and its human P-glycoprotein overexpressing mutant LLC-PK1/MDR1 cells (2008a). They investigated whether the P-glycoprotein, a member of the adenosine triphosphate-binding cassette transporter superfamily that has been found in a large number of normal tissues including intestine, liver, placenta, kidney, and the blood-brain barrier (BBB), interacts in the drug transport of ATX, MPH, amphetamine, and modafinil (Zhu et al 2008a). Since it is known that in the BBB, P-glycoprotein prohibits substrate drug penetration into the CNS van Asperen et al 1997 of CES1 is located in codon 143 and leads to a non-conservative substitution (Gly143Glu), which results in a reduction of enzyme activity and complete loss of hydrolytic activity toward methylphenidate.…”