Thc metabolism
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THC Metabolism: An Overview
Introduction to THC Metabolism
Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. Understanding its metabolism is crucial for predicting its effects and potential interactions with other substances. THC metabolism involves various enzymes and occurs in multiple tissues, including the liver, intestines, and lungs.
Hepatic Metabolism of THC
Enzymes Involved in Liver Metabolism
The liver is the primary site for THC metabolism. Key enzymes involved include cytochrome P450 (CYP) isoforms, particularly CYP2C9 and CYP3A4, and UDP-glucuronosyltransferases (UGTs). CYP2C9 is the major enzyme responsible for the hydroxylation of THC to 11-hydroxy-THC (11-OH-THC), a psychoactive metabolite . This metabolite is further oxidized to 11-nor-9-carboxy-THC (THCCOOH), an inactive form .
Kinetics and Pharmacogenetics
The kinetics of THC metabolism in the liver show that CYP2C9 has a high affinity for THC, with a Km of approximately 2 µM. Variants of CYP2C9, such as CYP2C9.2 and CYP2C9.3, exhibit lower intrinsic clearance rates compared to the wild type, which can affect the overall metabolism rate of THC. Additionally, UGTs play a significant role in the metabolism of 11-OH-THC, contributing to its clearance from the body.
Extrahepatic Metabolism of THC
Intestinal and Fetal Liver Metabolism
THC is also metabolized in extrahepatic tissues such as the intestines and fetal liver. In the intestines, CYP2C9 and CYP3A enzymes are involved in the metabolism of THC and 11-OH-THC. In fetal liver microsomes, CYP3A is the predominant enzyme responsible for the metabolism of both THC and 11-OH-THC.
Lung and Placenta Metabolism
Interestingly, significant metabolism of THC and 11-OH-THC was not observed in adult lung or placental microsomes, indicating that these tissues may not play a major role in the metabolism of THC.
In Vitro and In Vivo Studies
Animal Models
Studies using rat liver homogenates have shown that THC is metabolized to several hydroxylated products, with 7-hydroxy-THC being a major metabolite. These metabolites are further processed into more polar compounds, which are excreted primarily through bile.
Human Studies
Human studies have confirmed that the general pattern of THC metabolism is consistent across different routes of administration, including intravenous, oral, and smoking . After oral administration, both THC and 11-OH-THC are formed in significant quantities, whereas smoking results in lower levels of 11-OH-THC .
Implications for Drug Interactions
THC can interact with other drugs metabolized by the same enzymes. For instance, THC has been shown to increase the rate of phenytoin hydroxylation, suggesting a potential interaction that could affect phenytoin levels in the body. This highlights the importance of understanding THC metabolism for predicting drug-drug interactions.
Conclusion
THC metabolism is a complex process involving multiple enzymes and tissues. The liver plays a central role, with CYP2C9 and CYP3A4 being key enzymes. Extrahepatic tissues like the intestines and fetal liver also contribute to THC metabolism. Understanding these pathways is essential for predicting the pharmacokinetics of THC and its interactions with other drugs.
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