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

• Published in: Neuropsychiatric disease and treatment Vol. 7; no. 1; pp. 501 - 505
• Main Authors: Markowitz, John, Zhu
• Format: Journal Article
• Language: English
• Published: New Zealand Taylor & Francis Ltd 01.01.2011; Dove Press; Dove Medical Press
• Subjects: Attention deficit hyperactivity disorder; Glycoproteins; guanfacine; intracellular uptake; Original Research; P-glycoprotein; substrate; P-glycoprotein; intracellular uptake; guanfacine; substrate
• ISSN: 1176-6328; 1178-2021; 1176-6328; 1178-2021
• DOI: 10.2147/NDT.S24153

With a US Food and Drug Administration-labeled indication to treat attention-deficit/hyperactivity disorder (ADHD), the nonstimulant guanfacine has become the preferred α(2)-agonist for ADHD treatment. However, significant interindividual variability has been observed in response to guanfacine. Consequently, hypotheses of a contributing interaction with the ubiquitously expressed drug transporter, P-glycoprotein (P-gp), have arisen. We performed an in vitro study to determine if guanfacine is indeed a substrate of P-gp. Intracellular accumulation of guanfacine was compared between P-gp expressing LLC-PK1/MDR1 cells and P-gp-negative LLC-PK1 cells to evaluate the potential interaction between P-gp and guanfacine. Cellular retention of guanfacine was analyzed using a high-performance liquid chromatographic-ultraviolet method. Rhodamine6G, a known P-gp substrate, was included in the study as a positive control. At guanfacine concentrations of 50 μM and 5 μM, intracellular accumulation of guanfacine in LLC-PK1/MDR1 cells was, 35.9% ± 4.8% and 49.0% ± 28.3% respectively, of that in LLC-PK1 cells. In comparison, the concentration of rhodamine6G, the positive P-gp substrate, in LLC-PK1/MDR1 cells was only 5% of that in LLC-PK1 cells. The results of the intracellular accumulation study suggest that guanfacine is, at best, a weak P-gp substrate. Therefore, it is unlikely that P-gp, or any genetic variants thereof, are a determining factor in the interindividual variability of response observed with guanfacine therapy.