Savvy Psychopharmacology

CYP450 interactions between illicit substances and prescription medications


 

References

Cocaine is largely metabolized by serum esterases such as pseudocholinesterase, human carboxylesterase-1 (hCE-1), and human carboxylesterase-2 (hCE-2), to inactive metabolites benzoylecgonine (35% to 45%) and ecgonine (32% to 49%).2 However, a smaller portion (2.6% to 6.2%) undergoes hepatic N-demethylation by CYP3A4 to norcocaine.3 Norcocaine is an active metabolite responsible for some of the toxic effects of cocaine (eg, hepatotoxicity).4,5 Several commonly prescribed medications are known inducers of CYP3A4 (eg, phenytoin, carbamazepine) and may lead to increased levels of the toxic metabolite when used concurrently with cocaine. Additionally, the use of cocaine with acetylcholinesterase inhibitors, such as donepezil, may lead to reduction of serum esterases and shunt cocaine metabolism toward the hepatic pathway, thus increasing norcocaine formation.3

Cannabis. The metabolism and drug–drug interactions of cannabis can be separated by its 2 main components: delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). A review conducted in 2014 concluded that THC is primarily metabolized by CYP2C9 and 3A4, while CBD is metabolized by CYP2C19 and 3A4.6 Oral administration of ketoconazole, a CYP3A4 inhibitor, along with cannabis extract has been shown to increase the maximum concentration (Cmax) and area under the curve (AUC) of THC by 1.2- and 1.8-fold, respectively, while increasing both Cmaxand AUC of CBD by 2-fold.6 In addition, CYP2C9 poor metabolizers have been shown to experience significant increases in THC exposure and reductions in metabolite formation, further supporting the role of CYP enzymes in cannabis metabolism.6

There is also evidence of enzyme induction by cannabis. Individuals who reported smoking marijuana experienced greater clearance of theophylline, a substrate of CYP1A2, than did those who reported not smoking marijuana.1,6 As with cigarette smoking, this effect appears to be a direct result of the hydrocarbons found in marijuana smoke rather than the cannabis itself, as there is a lack of evidence for enzyme induction when the drug is orally ingested.6

Amphetamine and methamphetamine appear to be both substrates and competitive inhibitors of CYP2D6.7 Rats administered quinidine (a strong 2D6 inhibitor) had 2-fold elevations in AUC and decreased clearance of amphetamine and its metabolites.8 Amphetamine-related recreational drugs, such as 3,4-methylenedioxy-methamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA), are substrates of CYP2D6 and CYP3A4, while MDMA also undergoes substantial metabolism by CYP1A2.3,7,9

Opioids. Heroin is metabolized to 6‑monoacetylmorphine (6-MAM) and morphine by hCE-1, hCE-2, and pseudocholinesterase, and has minimal impact on CYP enzymes. However, while morphine is primarily metabolized to inactive metabolites by UGT2B7, it does undergo minor metabolism through CYP3A4 and 2C8 pathways, creating potential for drug interactions with medications that inhibit or induce CYP3A4.10

Continue to: An underappreciated risk of illicit substance use

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