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delta-9-Tetrahydrocannabinol (Δ9-THC), the primary psychoactive constituent of marijuana, is subject to first pass hepatic metabolism primarily by hydroxylation to yield both active and inactive oxygenated products. The primary metabolite is formed via oxidation of the allylic methyl group to yield 11-hydroxy-Δ9-THC (THC-OH), which is further metabolized to 11-nor-9-carboxy-Δ9-THC (THC-COOH). The formation of THC-OH is mediated in part by CYP2C9. However, no studies have been conducted that focus on the human metabolism of Δ 9-THC with specific attention given to CYP2C enzyme kinetics. Expressed CYP2C9.1 exhibits high affinity for the hydroxylation of Δ9-THC (apparent Km of 2 μM), similar to that observed in human liver microsomes (apparent Km of 0.8 μM). In contrast, the calculated intrinsic clearance (apparent Vm/Km) for CYP2C9.2 and CYP2C9.3 was 33% and 27% that of the wild type, CYP2C9.1, respectively. In addition, CYP2C19 was found to catalyze the formation of THC-OH, although it did so much less efficiently than CYP2C9.1 as demonstrated by a calculated intrinsic clearance equal to 30% of that observed with CYP2C9.1. Given the high affinity of CYP2C9 for the hydroxylation of Δ 9-THC, we evaluated the potential for drug-drug interactions between Δ 9-THC, THC-OH, or THC-COOH and CYP2C9 substrates, phenytoin and warfarin. Δ 9-THC and THC-OH had a slight inhibitory effect on warfarin metabolism, as expected. Conversely, Δ9-THC increased the human liver microsomal metabolism of phenytoin, with comparable changes observed in expressed CYP2C9 enzyme, confirming the involvement of CYP2C9 in this process. Additionally, both THC-OH, and THC-COOH, similar to Δ9-THC, were found to activate phenytoin hydroxylation in human liver microsomes. On the other hand, phenytoin had little effect on the conversion of Δ 9-THC to THC-OH in human liver microsomes. Our in vitro data suggest the potential for an interaction with the concomitant administration of Δ9-THC and phenytoin that could result in decreased phenytoin concentrations in vivo. To our knowledge, this is the first observation of a commonly abused illicit substance serving to increase the metabolism of a widely prescribed medication.