PT-027 - INHIBITION OF TACROLIMUS METABOLISM BY CANNABIDIOL AND ITS METABOLITES IN VITRO.

G. So, J. Lu, Y. Cheng, D. Gisch, T. Beamon, M. Eadon, Z. Desta; Indiana University, Indianapolis, IN, USA.

Background: Tacrolimus is metabolized by CYP3A4/5. Cannabidiol, derived from hemp, is widely used to treat a variety of conditions and may be taken with tacrolimus. This study seeks to characterize the inhibitory effect of cannabidiol and its metabolites on tacrolimus metabolism.

Methods: The effect of 10 μM cannabidiol, 7-hydroxycannabidiol, and 7-carboxycannabidiol on tacrolimus (1 μM) depletion was determined using pooled human liver microsomes (HLMs) and expressed CYP3A4 and CYP3A5 enzymes. Inhibition of tacrolimus depletion by ketoconazole (1 μM) was used as a positive control. Parent percent remaining was plotted on a semi-log scale from which linear regression analysis was performed to calculate or extrapolate the depletion rate constant (kdep), half-life (t1/2), and intrinsic clearances. Statistical significance of inhibition was assessed by ANOVA with Dunnett’s T3 multiple comparison testing corrected for multiplicity (p < 0.05).

Results: In pooled HLMs, expressed CYP3A4, and expressed CYP3A5, tacrolimus depletion yielded t1/2 of 2.54, 0.922, and 0.351 min, respectively. In pooled HLMs, cannabidiol and 7-hydroxycannabidiol moderately increased tacrolimus t1/2 by 1.79- and 3.30-fold, respectively, while ketoconazole prolonged t1/2 by 11.2-fold. In expressed CYP3A4, 7-hydroxycannabidiol, cannabidiol, and ketoconazole prolonged tacrolimus t1/2 by 15.2-, 6.63-, and 8.74-fold, respectively. In expressed CYP3A5, cannabidiol, 7-hydroxycannabidiol, and ketoconazole prolonged t1/2 by 30.3-, 20.1-, and 2.74-fold, respectively. In all experiments, 7-carboxycannabidiol consistently had minimal effect on tacrolimus depletion. Statistically significant inhibition of tacrolimus depletion by cannabidiol, 7-hydroxycannabidiol, and ketoconazole were shown across all incubation systems (p < 0.0001 in pooled HLMs and expressed CYP3A4; p < 0.05 in expressed CYP3A5).

Conclusion: This study provides in vitro evidence that cannabidiol and 7-hydroxycannabidiol strongly inhibit tacrolimus metabolism, whereas 7-carboxycannabidiol had minimal inhibition. We also found that cannabidiol and 7-hydroxycannabidiol showed stronger inhibition in expressed CYP3A5 compared to ketoconazole. The clinical relevance of this in vitro finding will be tested in an ongoing clinical tacrolimus and cannabidiol drug-drug interaction study.