Journal
BIOCHEMICAL PHARMACOLOGY
Volume 70, Issue 7, Pages 1096-1103Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2005.07.007
Keywords
CYP2C; tetrahydrocannabinol; phenytoin; drug interaction; drug metabolism; pharmacogenetics
Categories
Funding
- NIDDK NIH HHS [N01-DK-6-2274] Funding Source: Medline
- NIGMS NIH HHS [GM63215] Funding Source: Medline
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delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the primary psychoactive constituent of marijuana, is subject to first pass hepatic metabolism primarily by hydroxylation to yield active and inactive oxygenated products. The primary metabolite is formed via oxidation of the allylic methyl group to yield 11 -hydroxy-Delta(9)-THC, which is oxidized further to 11-nor-9-carboxy-Delta(9)-THC. The hydroxylation is thought to be mediated by CYP2C9. The present study was designed to address the kinetics and pharmacogenetics of CYP2C-mediated metabolism of (Delta(9))-THC by studying its metabolism in human liver microsomes and expressed enzymes. Expressed CYP2C9.1 exhibited high affinity for the hydroxylation of Delta(9)-THC (apparent Km, 2 mu M), similar to that observed in human liver microsomes (apparent K-m, 0.8 mu M). In contrast, the calculated intrinsic clearance (apparent V-m/K-m.) for CYP2C9.2 and CYP2C9.3 was approximately 30% that of the wild type, CYP2C9.1. Given the high affinity of CYP2C9 for the hydroxylation of Delta(9)-THC, we evaluated the potential for an interaction between Delta(9)-THC, I I -hydroxy-Delta(9)-THC, or 11 -nor-9-carboxy-Delta(9)-THC and the CYP2C9 substrate, phenytoin. Surprisingly, Delta(9)-THC increased the rate of phenytoin hydroxylation in human liver microsomes and expressed CYP2C9 enzyme. Similar increases in rate were observed with co-incubation of 11-hydroxy-Delta(9)-THC and 11-nor-9-carboxy-Delta(9)-THC with phenytoin. These in vitro data suggest the potential for an interaction from the concomitant administration of Delta(9)-THC and phenytoin that could result in decreased phenytoin concentrations in vivo. (c) 2005 Elsevier Inc. All rights reserved.
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