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Home , CYP3A4, Cytochrome P450

Savvy Psychopharmacology

CYP450 interactions between illicit substances and prescription medications

Megan O’Connell, PharmD, BCPP, and Amy VandenBerg, PharmD, BCPP

s. L, age 37, presents to psychiatric Because Ms. L’s level is <350 and emergency services with command her ratio is approximately 1:1, her clozapine M auditory hallucinations, ideas of treatment is subtherapeutic. reference, and suicidal ideation. Because Ms. L has a history of documented Ms. L has a 22-year history of . adherence to and benefit from her current Additionally, she has a history of use medication regimen, no changes are made disorder (in remission for 12 years), cannabis during her 3-week hospital stay. She notices Vicki L. Ellingrod, use disorder (in remission for 6 months), type a gradual reduction in auditory hallucina- PharmD, FCCP 2 diabetes mellitus, and hypertension. Her psy- tions, no longer wants to harm herself, and is Department Editor chotic symptoms are well controlled on a regi- motivated to regain sobriety. men of clozapine, 700 mg/d, and paliperidone At the time of discharge, Ms. L’s clozapine palmitate, 156 mg/month. Ms. L says she has and norclozapine trough levels are 550 and been adherent to these medications, and this 250 ng/mL, respectively, which indicates a is confirmed by the assertive community treat- more favorable clozapine-to-norclozapine ment (ACT) team member who administers the ratio of approximately 2:1 and a clozapine medications at Ms. L’s home each day. level greater than the recommended mini- On interview, Ms. L reports smoking mum threshold of 350 ng/mL. While cocaine cannabis each day for the past month and ingestion presumably played a role in her using $400 worth of cocaine over 2 days. acute decompensation, the treatment team She is experiencing intense guilt over these relapses and is admitted to the inpatient Practice Points adult psychiatry unit. On admission, Ms. L’s • Many common illicit substances clozapine and norclozapine trough levels are metabolized to some degree by (drawn approximately 12 hours after last the P450 (CYP) administration documented by the ACT system. This puts patients at risk for member) are 300 and 275 ng/mL, respec- –drug interactions when using illicit tively. Generally, clozapine levels >350 to 420 substances concurrently with prescription ng/mL are considered therapeutic, and a clo- medications that induce or inhibit these . Savvy Psychopharmacology zapine-to-norclozapine ratio of 2:1 is desir- is produced in partnership able for maximum efficacy and tolerability. • The active and toxic metabolite of cocaine, with the College norcocaine, is created when cocaine is of Psychiatric metabolized by CYP3A4. The concurrent and Neurologic Dr. O’Connell is a Clinical Pharmacist, University of Kansas Hospital, Pharmacists Kansas City, Kansas. Dr. VandenBerg is a Clinical Specialist, use of strong CYP3A4 inducers with cpnp.org Psychiatry and Neurology, Michigan , University of cocaine lead to higher levels of this mhc.cpnp.org (journal) Michigan, Ann Arbor, Michigan. toxic metabolite. Disclosures The authors report no financial relationships with any companies • Similar to cigarette smoke, the whose products are mentioned in this article, or with manufacturers hydrocarbons in cannabis smoke Current Psychiatry of competing products. appear to induce CYP1A2 activity. 40 August 2020 doi: 10.12788/cp.0028 Savvy Psychopharmacology

Table of illicit substances Substance Metabolism Induces Inhibits Cocaine Esterases, 3A4 Cannabis 1A2 (smoke) THC 2C9, 3A4 CBD 2C19, 3A4 MDMA 1A2 > 2D6, 3A4 Amphetamine/methamphetamine 2D6 2D6 Heroin Esterases UGT2B7, 3A4, 2C8 Clinical Point CBD: ; MDMA: 3,4-methylenedioxy-methamphetamine; THC: delta-9- Source: References 1-8 When used concurrently with cocaine, CYP3A4 determined that Ms. L’s relapse to cannabis Cocaine is largely metabolized by serum inducers may lead to use likely contributed to low clozapine levels esterases such as pseudocholinesterase, increased levels of by induction of (CYP) 1A2, human carboxylesterase-1 (hCE-1), and the toxic metabolite and subsequently led to the delayed recov- human carboxylesterase-2 (hCE-2), to inac- ery of symptom control.1 tive metabolites benzoylecgonine (35% to norcocaine 45%) and ecgonine (32% to 49%).2 However, The use of illicit substances is a widespread, a smaller portion (2.6% to 6.2%) undergoes growing problem. According to the 2017 hepatic N- by CYP3A4 to nor- National Survey on Drug Use and Health, cocaine.3 Norcocaine is an active metabolite 11.5% of Americans age ≥12 had used responsible for some of the toxic effects of an illicit substance (ie, use of marijuana, cocaine (eg, ).4,5 Several com- cocaine, heroin, hallucinogens, inhalants, monly prescribed medications are known or methamphetamine, or misuse of pre- inducers of CYP3A4 (eg, , carbam- scription psychotherapeutics) in the past azepine) and may lead to increased levels of month.2 While illicit substance use is of the toxic metabolite when used concurrently particular public health interest due to a with cocaine. Additionally, the use of cocaine known increase in mortality and health care with acetylcholinesterase inhibitors, such as spending, there has been little discussion of , may lead to reduction of serum the impact of illicit drug use on concurrent esterases and shunt cocaine metabolism pharmacologic therapy. Just as prescription toward the hepatic pathway, thus increasing medications have pharmacokinetic drug– norcocaine formation.3 drug interactions with each other, so do illicit substances, though far less is known Cannabis. The metabolism and drug–drug about their impact on the treatment of med- interactions of cannabis can be separated ical conditions. by its 2 main components: delta-9-tetra- Discuss this article at hydrocannabinol (THC) and cannabidiol www.facebook.com/ MDedgePsychiatry Pharmacokinetic interactions (CBD). A review conducted in 2014 con- Key pharmacokinetic interactions have cluded that THC is primarily metabo- been reported with cocaine, marijuana, lized by CYP2C9 and 3A4, while CBD is amphetamines, and . The Table1-8 metabolized by CYP2C19 and 3A4.6 Oral summarizes the metabolism of illicit administration of , a CYP3A4 Current Psychiatry substances. inhibitor, along with cannabis extract has Vol. 19, No. 8 41 Savvy Psychopharmacology

3,4-methylenedioxy-methamphetamine Related Resources (MDMA) and 3,4-methylenedioxyamphet- • Lindsey W, Stewart D, Childress D. Drug interactions amine (MDA), are substrates of CYP2D6 between common illicit and prescription therapies. Am J Drug Abuse. 2012;38(4):334-343. and CYP3A4, while MDMA also undergoes 3,7,9 • Maurer H, Sauer C, Theobald D. Toxicokinetics of drugs of substantial metabolism by CYP1A2. abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, . cocaine, heroin, morphine, and . Ther Drug Monit. Opioids Heroin is metabolized to 6‑mono- 2006;28(3):447-453. acetylmorphine (6-MAM) and morphine by • Dean A. Illicit drugs and drug interactions. Pharmacist. hCE-1, hCE-2, and pseudocholinesterase, 2006;25(9):684-689. and has minimal impact on CYP enzymes. Drug Brand Names However, while morphine is primarily • Carbatrol, Phenytoin • Dilantin, metabolized to inactive metabolites by Tegretol Phenytek Clinical Point Clozapine • Clozaril • Cardioquin, UGT2B7, it does undergo minor metabo- Donepezil • Aricept Duraquin lism through CYP3A4 and 2C8 pathways, Amphetamine- Ketoconazole • Nizoral Theophylline • Elixophylline, Paliperidone palmitate • Theochron creating potential for drug interactions with related recreational Invega sustenna medications that inhibit or induce CYP3A4.10 drugs such as MDMA are substrates of An underappreciated risk of illicit CYP2D6 and CYP3A4 substance use been shown to increase the maximum There is a paucity of evidence regarding concentration (Cmax) and area under the the metabolism and pharmacokinetic inter- curve (AUC) of THC by 1.2- and 1.8-fold, actions with illicit substances, and further

respectively, while increasing both Cmax research is needed. Despite the absence of and AUC of CBD by 2-fold.6 In addition, comprehensive data on the subject, the avail- CYP2C9 poor metabolizers have been able information indicates the use of illicit shown to experience significant increases substances may have a significant impact on in THC exposure and reductions in metab- medications used to treat comorbid condi- olite formation, further supporting the role tions. Alternatively, those medications may of CYP enzymes in cannabis metabolism.6 affect the kinetics of recreationally used sub- There is also evidence of enzyme induc- stances. The risk of adverse consequences of tion by cannabis. Individuals who reported drug–drug interactions is yet another reason smoking marijuana experienced greater patients should be encouraged to avoid use of theophylline, a of of substances and seek treatment for sub- CYP1A2, than did those who reported not stance use disorders. When determining smoking marijuana.1,6 As with cigarette the most appropriate therapy for comorbid smoking, this effect appears to be a direct conditions for patients who are using illicit result of the hydrocarbons found in mari- substances and are likely to continue to do juana smoke rather than the cannabis itself, so, clinicians should take into consideration as there is a lack of evidence for enzyme potential interactions among prescription induction when the drug is orally ingested.6 medications and the specific illicit substances the patient uses. Amphetamine and methamphetamine appear to be both substrates and com- References 7 1. Jusko WJ, Schentag JJ, Clark JH, et al. Enhanced petitive inhibitors of CYP2D6. of theophylline in marihuana and tobacco administered quinidine (a strong 2D6 smokers. Clin Pharmacol Ther. 1978;24(4):405-410. inhibitor) had 2-fold elevations in AUC 2. Substance Abuse and Mental Health Services Administration. Results from the 2017 National Survey and decreased clearance of amphetamine on Drug Use and Health: Detailed Tables. https://www. and its metabolites.8 Amphetamine- samhsa.gov/data/sites/default/files/cbhsq-reports/ Current Psychiatry NSDUHDetailedTabs2017/NSDUHDetailedTabs2017. 42 August 2020 related recreational drugs, such as htm#tab1-1A. Published 2019. Accessed February 7, 2020. continued on page 51 Savvy Psychopharmacology

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3. Quinn D, Wodak A, Day R. Pharmacokinetic and pharmacody- 7. Kraemer T, Maurer H. Toxicokinetics of amphetamines: namic principles of illicit drug use and treatment of illicit and toxicokinetic data of designer drugs, users. Clin Pharmacokinet. 1997;33(5):344-400. amphetamine, methamphetamine, and their N-alkyl 4. Ndikum-Moffor FM, Schoeb TR, Roberts SM. toxicity derivatives. Ther Drug Monit. 2002;24(2):277-289. from norcocaine nitroxide, an N-oxidative metabolite of 8. Markowitz J, Patrick K. Pharmacokinetic and pharmacody- cocaine. J Pharmacol Exp Ther. 1998;284(1):413-419. namic drug interactions in the treatment of attention-deficit 5. Pellinen P, Honkakoski P, Stenbäck F, et al. Cocaine hyperactivity disorder. Clin Pharmacokinet. 2001;40(10):753-772. N-demethylation and the metabolism-related hepatotoxicity 9. Kreth K, Kovar K, Schwab M, et al. Identification of the human can be prevented by cytochrome P450 3A inhibitors. Eur J P450 involved in the oxidative metabolism Pharmacol. 1994;270(1):35-43. of “ecstasy”-related designer drugs. Biochem Pharmacol. 6. Stout S, Cimino N. Exogenous as substrates, 2000;59(12):1563-1571. inhibitors, and inducers of human drug metabolizing 10. Meyer M, Maurer H. Absorption, distribution, metabolism enzymes: a systematic review. Drug Metab Rev. 2013;46(1): and of drugs of abuse. 86-95. Pharmacogenomics. 2011;12(2):215-233.

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