@article {NasrinDMD-AR-2021-000530, author = {Shamema Nasrin and Christy J.W. Watson and Keti Bardhi and Gabriela Fort and Gang Chen and Philip Lazarus}, title = {Inhibition of UDP-glucuronosyltransferase enzymes by major cannabinoids and their metabolites}, elocation-id = {DMD-AR-2021-000530}, year = {2021}, doi = {10.1124/dmd.121.000530}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The UDP-glucuronosyltransferase (UGT) family of enzymes play a central role in the metabolism and detoxification of a wide range of endogenous and exogenous compounds. UGTs exhibit a high degree of structural similarity and display overlapping substrate specificity, often making estimations of potential drug-drug interactions difficult to fully elucidate. One such interaction yet to be examined may be occurring between UGTs and cannabinoids, as the legalization of recreational and medicinal cannabis and subsequent co-usage of cannabis and therapeutic drugs increases in the U.S. and internationally. In the present study, the inhibition potential of the major cannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), as well as their major metabolites, was determined in microsomes isolated from HEK293 cells over-expressing individual recombinant UGTs and in microsomes from human liver and kidney specimens. The highest inhibition was seen by CBD against the glucuronidation activity of UGTs 1A9, 2B4,1A6 and 2B7, with binding- corrected IC50,u values of 0.12 {plus minus} 0.020 {\textmu}M, 0.22 {plus minus} 0.045 {\textmu}M, 0.40 {plus minus} 0.10 {\textmu}M and 0.82 {plus minus} 0.15 {\textmu}M, respectively. Strong inhibition of UGT1A9 was also demonstrated by THC and CBN, with IC50,u values of 0.45 {plus minus} 0.12 {\textmu}M and 0.51 {plus minus} 0.063 {\textmu}M, respectively. Strong inhibition of UGT2B7 was also observed for THC and CBN; no or weak inhibition was observed with cannabinoid metabolites. This inhibition of UGT activity suggests that in addition to playing an important role in drug-drug interactions, cannabinoid exposure may have important implications in patients with impaired hepatic or kidney function. Significance Statement Major cannabinoids found in the plasma of cannabis users inhibit several UGT enzymes, including UGT1A6, UGT1A9, UGT2B4, and UGT2B7. This study is the first to show the potential of cannabinoids and their metabolites to inhibit all major kidney UGTs and the two most abundant UGTs present in liver. This study suggests that as all three major kidney UGTs are inhibited by cannabinoids, greater drug-drug interaction effects might be observed from co-use of cannabinoids and therapeutics that are cleared renally.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2021/09/07/dmd.121.000530}, eprint = {https://dmd.aspetjournals.org/content/early/2021/09/07/dmd.121.000530.full.pdf}, journal = {Drug Metabolism and Disposition} }