Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein.
The objective of this study was to assess the potential interactions of the drug transporter P-glycoprotein 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 P-glycoprotein 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, d-modafinil, and l-modafinil.
Zhu
Hao-Jie
HJ
Laboratory of Drug Disposition and Pharmacogenetics, Medical University of South Carolina, USA.
Wang
Jun-Sheng
JS
Donovan
Jennifer L
JL
Jiang
Yan
Y
Gibson
Bryan B
BB
DeVane
C Lindsay
CL
Markowitz
John S
JS
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000661:Amphetamine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000378:metabolism; D001559:Benzhydryl Compounds / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D003524:Cyclosporins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism; D007536:Isomerism; D018374:LLC-PK1 Cells; D008774:Methylphenidate / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000077408:Modafinil; D011437:Propylamines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015203:Reproducibility of Results; D020112:Rhodamine 123 / Q000378:metabolism; D013552:Swine; D014162:Transfection
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D003524:Cyclosporins; D011437:Propylamines; D020112:Rhodamine 123; D008774:Methylphenidate; D000069445:Atomoxetine Hydrochloride; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D000661:Amphetamine; C070272:valspodar; D000077408:Modafinil