DOCSLIB.ORG

CYP450 Interactions Between Illicit Substances and Prescription Medications

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
CYP450 Interactions Between Illicit Substances and Prescription Medications 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 clozapine 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 schizophrenia. adherence to and benefit from her current Additionally, she has a history of cocaine 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 cytochrome P450 (CYP) enzyme administration documented by the ACT system. This puts patients at risk for member) are 300 and 275 ng/mL, respec- drug–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 enzymes. 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 Medicine, 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 Metabolism 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 Morphine UGT2B7, 3A4, 2C8 Clinical Point CBD: cannabidiol; MDMA: 3,4-methylenedioxy-methamphetamine; THC: delta-9-tetrahydrocannabinol 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 cytochrome P450 (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-demethylation 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, hepatotoxicity).4,5 Several com- cocaine, heroin, hallucinogens, inhalants, monly prescribed medications are known or methamphetamine, or misuse of pre- inducers of CYP3A4 (eg, phenytoin, 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 donepezil, 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 opioids. The Table1-8 metabolized by CYP2C19 and 3A4.6 Oral summarizes the metabolism of illicit administration of ketoconazole, 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 drugs and prescription therapies. Am J Drug Alcohol 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 codeine. 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 Carbamazepine • Carbatrol, Phenytoin • Dilantin, metabolized to inactive metabolites by Tegretol Phenytek Clinical Point Clozapine • Clozaril Quinidine • 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 clearance of theophylline, a substrate 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
Load more

Recommended publications
  • Impaired Hepatic Drug and Steroid Metabolism in Congenital Adrenal
    European Journal of Endocrinology (2010) 163 919–924 ISSN 0804-4643 CLINICAL STUDY Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency Dorota Tomalik-Scharte1, Dominique Maiter2, Julia Kirchheiner3, Hannah E Ivison, Uwe Fuhr1 and Wiebke Arlt School of Clinical and Experimental Medicine, Centre for Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK, 1Department of Pharmacology, University Hospital, University of Cologne, 50931 Cologne, Germany, 2Department of Endocrinology, University Hospital Saint Luc, 1200 Brussels, Belgium and 3Department of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, 89019 Ulm, Germany (Correspondence should be addressed to W Arlt; Email: [email protected]) Abstract Objective: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drug- metabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied. Design: We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer. Methods: Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes.
    [Show full text]
  • Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid
    Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 231 _____________________________ _____________________________ Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid Cloning, Expression and Catalytic Properties of CYP4F8 and CYP4F21 BY JOHAN BYLUND ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2000 Dissertation for the Degree of Doctor of Philosophy (Faculty of Pharmacy) in Pharmaceutical Pharmacology presented at Uppsala University in 2000 ABSTRACT Bylund, J. 2000. Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid: Cloning, Expression and Catalytic Properties of CYP4F8 and CYP4F21. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from Faculty of Pharmacy 231 50 pp. Uppsala. ISBN 91-554-4784-8. Cytochrome P450 (P450 or CYP) is an enzyme system involved in the oxygenation of a wide range of endogenous compounds as well as foreign chemicals and drugs. This thesis describes investigations of P450-catalyzed oxygenation of prostaglandins, linoleic and arachidonic acids. The formation of bisallylic hydroxy metabolites of linoleic and arachidonic acids was studied with human recombinant P450s and with human liver microsomes. Several P450 enzymes catalyzed the formation of bisallylic hydroxy metabolites. Inhibition studies and stereochemical analysis of metabolites suggest that the enzyme CYP1A2 may contribute to the biosynthesis of bisallylic hydroxy fatty acid metabolites in adult human liver microsomes. 19R-Hydroxy-PGE and 20-hydroxy-PGE are major components of human and ovine semen, respectively. They are formed in the seminal vesicles, but the mechanism of their biosynthesis is unknown. Reverse transcription-polymerase chain reaction using degenerate primers for mammalian CYP4 family genes, revealed expression of two novel P450 genes in human and ovine seminal vesicles.
    [Show full text]
  • Mechanism of Inhibition of Cytochrome P450 C21 Enzyme Activity By
    European Journal of Endocrinology (2005) 152 95–101 ISSN 0804-4643 CLINICAL STUDY Mechanism of inhibition of cytochrome P450 C21 enzyme activity by autoantibodies from patients with Addison’s disease L Nikfarjam1, S Kominami1, T Yamazaki1, S Chen2, R Hewer2, C Dal Pra2,3, T Nakamatsu2,3, C Betterle4, R Zanchetta4, B Rees Smith2,3 and J Furmaniak2,3 1Faculty of Integrated Arts and Sciences, Hiroshima University, Higashihiroshima, 739-8521 Japan, 2FIRS Laboratories, RSR Ltd, Parc Ty Glas, Llanishen, Cardiff CF14 5DU, UK, 3Department of Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK and 4Department of Medical and Surgical Sciences, University of Padua, Via Ospedale Civile 105, 35128 Padua, Italy (Correspondence should be addressed to J Furmaniak, FIRS Laboratories, RSR Ltd, Parc Ty Glas, Llanishen, Cardiff CF14 5DU, UK; Email: fi[email protected]) Abstract Objective: To study possible mechanisms for the inhibition of cytochrome P450 C21 (steroid 21- hydroxylase) enzyme activity by P450 C21 autoantibodies (Abs) in vitro. Design: Two possible mechanisms for the inhibition of P450 C21 enzyme activity by P450 C21 Abs were studied: (a) conformational changes in the P450 C21 molecule induced by Ab binding and (b) the effects of Ab binding to P450 C21 on the electron transfer from the nicotinamide adenine dinu- cleotide phosphate reduced (NADPH) cytochrome P450 reductase (CPR) to P450 C21. Methods: The effect of P450 C21 Ab binding on the conformation of recombinant P450 C21 in yeast microsomes was studied using an analysis of the dithionite-reduced CO difference spectra. The effect of P450 C21 Abs on electron transfer was assessed by analysis of reduction of P450 C21 in the micro- somes in the presence of CO after addition of NADPH.
    [Show full text]
  • Regulation of Vitamin D Metabolizing Enzymes in Murine Renal and Extrarenal Tissues by Dietary Phosphate, FGF23, and 1,25(OH)2D3
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2018 Regulation of vitamin D metabolizing enzymes in murine renal and extrarenal tissues by dietary phosphate, FGF23, and 1,25(OH)2D3 Kägi, Larissa ; Bettoni, Carla ; Pastor-Arroyo, Eva M ; Schnitzbauer, Udo ; Hernando, Nati ; Wagner, Carsten A Abstract: BACKGROUND: The 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) together with parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) regulates calcium (Ca2+) and phosphate (Pi) homeostasis, 1,25(OH)2D3 synthesis is mediated by hydroxylases of the cytochrome P450 (Cyp) family. Vitamin D is first modified in the liver by the 25-hydroxylases CYP2R1 and CYP27A1 and further acti- vated in the kidney by the 1-hydroxylase CYP27B1, while the renal 24-hydroxylase CYP24A1 catalyzes the first step of its inactivation. While the kidney is the main organ responsible for circulating levelsofac- tive 1,25(OH)2D3, other organs also express some of these enzymes. Their regulation, however, has been studied less. METHODS AND RESULTS: Here we investigated the effect of several Pi-regulating factors including dietary Pi, PTH and FGF23 on the expression of the vitamin D hydroxylases and the vitamin D receptor VDR in renal and extrarenal tissues of mice. We found that with the exception of Cyp24a1, all the other analyzed mRNAs show a wide tissue distribution. High dietary Pi mainly upregulated the hep- atic expression of Cyp27a1 and Cyp2r1 without changing plasma 1,25(OH)2D3. FGF23 failed to regulate the expression of any of the studied hydroxylases at the used dosage and treatment length.
    [Show full text]
  • Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: from Discovery to Clinical Usage
    H OH metabolites OH Review Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage Yaping Wang 1, Xiaobo Li 2 and Shunlin Ren 1,* 1 Department of Internal Medicine, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23249, USA; [email protected] 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; [email protected] * Correspondence: [email protected]; Tel.: +1-(804)-675-5000 (ext. 4973) Abstract: Oxysterols have long been believed to be ligands of nuclear receptors such as liver × recep- tor (LXR), and they play an important role in lipid homeostasis and in the immune system, where they are involved in both transcriptional and posttranscriptional mechanisms. However, they are increas- ingly associated with a wide variety of other, sometimes surprising, cell functions. Oxysterols have also been implicated in several diseases such as metabolic syndrome. Oxysterols can be sulfated, and the sulfated oxysterols act in different directions: they decrease lipid biosynthesis, suppress inflammatory responses, and promote cell survival. Our recent reports have shown that oxysterol and oxysterol sulfates are paired epigenetic regulators, agonists, and antagonists of DNA methyl- transferases, indicating that their function of global regulation is through epigenetic modification. In this review, we explore our latest research of 25-hydroxycholesterol and 25-hydroxycholesterol 3-sulfate in a novel regulatory mechanism and evaluate the current evidence for these roles. Citation: Wang, Y.; Li, X.; Ren, S. Keywords: oxysterol sulfates; oxysterol sulfation; epigenetic regulators; 25-hydroxysterol; Cholesterol Metabolites 25-hydroxycholesterol 3-sulfate; 25-hydroxycholesterol 3,25-disulfate 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage.
    [Show full text]
  • TRANSLATIONALLY by AMPK a Dissertation
    CHOLESTEROL 7 ALPHA-HYDROXYLASE IS REGULATED POST- TRANSLATIONALLY BY AMPK A dissertation submitted to Kent State University in partial fulfillment of the requirements for the Degree of Doctor of Philosophy By Mauris E.C. Nnamani May 2009 Dissertation written by Mauris E. C. Nnamani B.S, Kent State University, 2006 Ph.D., Kent State University, 2009 Approved by Diane Stroup Advisor Gail Fraizer Members, Doctoral Dissertation Committee S. Vijayaraghavan Arne Gericke Jennifer Marcinkiewicz Accepted by Robert Dorman , Director, School of Biomedical Science John Stalvey , Dean, Collage of Arts and Sciences ii TABLE OF CONTENTS LIST OF FIGURES……………………………………………………………..vi ACKNOWLEDGMENTS……………………………………………………..viii CHAPTER I: INTRODUCTION……………………………………….…........1 a. Bile Acid Synthesis…………………………………………….……….2 i. Importance of Bile Acid Synthesis Pathway………………….….....2 ii. Bile Acid Transport..…………………………………...…...………...3 iii. Bile Acid Synthesis Pathway………………………………………...…4 iv. Classical Bile Acid Synthesis Pathway…..……………………..…..8 Cholesterol 7 -hydroxylase (CYP7A1)……..........………….....8 Transcriptional Regulation of Cholesterol 7 -hydroxylase by Bile Acid-activated FXR…………………………….....…10 CYP7A1 Transcriptional Repression by SHP-dependant Mechanism…………………………………………………...10 CYP7A1 Transcriptional Repression by SHP-independent Mechanism……………………………………..…………….…….11 CYP7A1 Transcriptional Repression by Activated Cellular Kinase…….…………………………...…………………….……12 v. Alternative/ Acidic Bile Acid Synthesis Pathway…………......…….12 Sterol 27-hydroxylase (CYP27A1)……………….…………….12
    [Show full text]
  • Functional Characterization of Eight Human Cytochrome P450 1A2 Gene Variants by Recombinant Protein Expression
    The Pharmacogenomics Journal (2010) 10, 478–488 & 2010 Macmillan Publishers Limited. All rights reserved 1470-269X/10 www.nature.com/tpj ORIGINAL ARTICLE Functional characterization of eight human cytochrome P450 1A2 gene variants by recombinant protein expression B Brito Palma1,2, M Silva e Sousa1, Inter-individual variability in cytochrome P450 (CYP)-mediated xenobiotic 2 2 metabolism is extensive. CYP1A2 is involved in the metabolism of drugs CR Vosmeer , J Lastdrager , and in the bioactivation of carcinogens. The objective of this study was 1 2 JRueff,NPEVermeulen to functionally characterize eight polymorphic forms of human CYP1A2, and M Kranendonk1 namely T83M, S212C, S298R, G299S, I314V, I386F, C406Y and R456H. cDNAs of these variants were constructed and coexpressed in Escherichia coli 1Department of Genetics, Faculty of Medical with human NADPH cytochrome P450 oxidoreductase (CYPOR). All variants Sciences, Universidade Nova de Lisbon, Lisbon, showed similar levels of apoprotein and holoprotein expression, except for Portugal and 2Division of Molecular Toxicology, Department of Pharmacochemistry, LACDR, Vrije I386F and R456H, which showed only apoprotein, and both were functionally Universiteit Amsterdam, Amsterdam, The inactive. The activity of CYP1A2 variants was investigated using 8 substrates, Netherlands measuring 16 different activity parameters. The resulting heterogeneous activity data set was analyzed together with CYP1A2 wild-type (WT) form, applying Correspondence: Dr M Kranendonk, Department of Genetics, multivariate analysis. This analysis indicated that variant G299S is substantially Faculty of Medical Sciences, Universidade Nova altered in catalytic properties in comparison with WT, whereas variant T83M is de Lisbon, Rua da Junqueira 96, 1349-008 slightly but significantly different from the WT.
    [Show full text]
  • Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice
    pharmaceutics Review Mechanisms of CYP450 Inhibition: Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice Malavika Deodhar 1, Sweilem B Al Rihani 1 , Meghan J. Arwood 1, Lucy Darakjian 1, Pamela Dow 1 , Jacques Turgeon 1,2 and Veronique Michaud 1,2,* 1 Tabula Rasa HealthCare Precision Pharmacotherapy Research and Development Institute, Orlando, FL 32827, USA; [email protected] (M.D.); [email protected] (S.B.A.R.); [email protected] (M.J.A.); [email protected] (L.D.); [email protected] (P.D.); [email protected] (J.T.) 2 Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada * Correspondence: [email protected]; Tel.: +1-856-938-8697 Received: 5 August 2020; Accepted: 31 August 2020; Published: 4 September 2020 Abstract: In an ageing society, polypharmacy has become a major public health and economic issue. Overuse of medications, especially in patients with chronic diseases, carries major health risks. One common consequence of polypharmacy is the increased emergence of adverse drug events, mainly from drug–drug interactions. The majority of currently available drugs are metabolized by CYP450 enzymes. Interactions due to shared CYP450-mediated metabolic pathways for two or more drugs are frequent, especially through reversible or irreversible CYP450 inhibition. The magnitude of these interactions depends on several factors, including varying affinity and concentration of substrates, time delay between the administration of the drugs, and mechanisms of CYP450 inhibition. Various types of CYP450 inhibition (competitive, non-competitive, mechanism-based) have been observed clinically, and interactions of these types require a distinct clinical management strategy. This review focuses on mechanism-based inhibition, which occurs when a substrate forms a reactive intermediate, creating a stable enzyme–intermediate complex that irreversibly reduces enzyme activity.
    [Show full text]
  • Potent Inhibition of Human Cytochrome P450 3A Isoforms by Cannabidiol: Role of Phenolic Hydroxyl Groups in the Resorcinol Moiety
    Life Sciences 88 (2011) 730–736 Contents lists available at ScienceDirect Life Sciences journal homepage: www.elsevier.com/locate/lifescie Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: Role of phenolic hydroxyl groups in the resorcinol moiety Satoshi Yamaori a, Juri Ebisawa a, Yoshimi Okushima a, Ikuo Yamamoto b, Kazuhito Watanabe a,c,⁎ a Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3, Kanagawa-machi, Kanazawa 920-1181, Japan b Department of Hygienic Chemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino-machi, Nobeoka 882-8508, Japan c Organization for Frontier Research in Preventive Pharmaceutical Sciences, Hokuriku University, Ho-3, Kanagawa-machi, Kanazawa 920-1181, Japan article info abstract Article history: Aims: In this study, we examined the inhibitory effects of Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol Received 4 October 2010 (CBD), and cannabinol (CBN), the three major cannabinoids, on the activity of human cytochrome P450 (CYP) Accepted 10 February 2011 3A enzymes. Furthermore, we investigated the kinetics and structural requirement for the inhibitory effect of CBD on the CYP3A activity. Keywords: Main methods: Diltiazem N-demethylase activity of recombinant CYP3A4, CYP3A5, CYP3A7, and human liver Cannabidiol microsomes (HLMs) in the presence of cannabinoids was determined. Δ9-Tetrahydrocannabinol Key findings: Among the three major cannabinoids, CBD most potently inhibited CYP3A4 and CYP3A5 Cannabinol μ Δ9 CYP3A4 (IC50 =11.7and1.65 M, respectively). The IC50 values of -THC and CBN for CYP3A4 and CYP3A5 were higher μ Δ9 – μ CYP3A5 than 35 M. For CYP3A7, -THC, CBD, and CBN inhibited the activity to a similar extent (IC50 =23 31 M).
    [Show full text]
  • Aripiprazole Therapy and CYP2D6 Genotype
    NLM Citation: Dean L. Aripiprazole Therapy and CYP2D6 Genotype. 2016 Sep 22. In: Pratt VM, Scott SA, Pirmohamed M, et al., editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-. Bookshelf URL: https://www.ncbi.nlm.nih.gov/books/ Aripiprazole Therapy and CYP2D6 Genotype Laura Dean, MD1 Created: September 22, 2016. Introduction Aripiprazole is an atypical antipsychotic used in the management of schizophrenia, bipolar disorder, major depressive disorder, irritability associated with autistic disorder, and treatment of Tourette’s disorder. The metabolism and elimination of aripiprazole is mainly mediated through two enzymes, CYP2D6 and CYP3A4. Approximately 8% of Caucasians, 3–8% of Black/African Americans and up to 2% of Asians cannot metabolize CYP2D6 substrates and are classified as “poor metabolizers” (1). The FDA-approved drug label for aripiprazole states that in CYP2D6 poor metabolizers, half of the usual dose should be administered. In CYP2D6 poor metabolizers who are taking concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin), a quarter of the usual dose should be used (Table 1) (2). Table 1. The FDA-recommended dose adjustments for aripiprazole in patients who are known CYP2D6 poor metabolizers and patients taking concomitant CYP2D6 inhibitors, CYP3A4 inhibitors, and/or CYP3A4 inducers (2016) Factors Dosage Adjustments for ABILIFY Known CYP2D6 Poor Metabolizers Administer half of usual dose Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors (e.g., Administer a quarter of usual dose itraconazole, clarithromycin) Strong CYP2D6 (e.g., quinidine, fluoxetine, paroxetine) or CYP3A4 inhibitors (e.g., Administer half of usual dose itraconazole, clarithromycin) Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP3A4 inducers (e.g., carbamazepine, rifampin) Double usual dose over 1 to 2 weeks Table is adapted from a FDA-approved drug label for aripiprazole (2).
    [Show full text]
  • Simulation of Physicochemical and Pharmacokinetic Properties of Vitamin D3 and Its Natural Derivatives
    pharmaceuticals Article Simulation of Physicochemical and Pharmacokinetic Properties of Vitamin D3 and Its Natural Derivatives Subrata Deb * , Anthony Allen Reeves and Suki Lafortune Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA; [email protected] (A.A.R.); [email protected] (S.L.) * Correspondence: [email protected] or [email protected]; Tel.: +1-224-310-7870 or +1-305-760-7479 Received: 9 June 2020; Accepted: 20 July 2020; Published: 23 July 2020 Abstract: Vitamin D3 is an endogenous fat-soluble secosteroid, either biosynthesized in human skin or absorbed from diet and health supplements. Multiple hydroxylation reactions in several tissues including liver and small intestine produce different forms of vitamin D3. Low serum vitamin D levels is a global problem which may origin from differential absorption following supplementation. The objective of the present study was to estimate the physicochemical properties, metabolism, transport and pharmacokinetic behavior of vitamin D3 derivatives following oral ingestion. GastroPlus software, which is an in silico mechanistically-constructed simulation tool, was used to simulate the physicochemical and pharmacokinetic behavior for twelve vitamin D3 derivatives. The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor and PKPlus modules were employed to derive the relevant parameters from the structural features of the compounds. The majority of the vitamin D3 derivatives are lipophilic (log P values > 5) with poor water solubility which are reflected in the poor predicted bioavailability. The fraction absorbed values for the vitamin D3 derivatives were low except for calcitroic acid, 1,23S,25-trihydroxy-24-oxo-vitamin D3, and (23S,25R)-1,25-dihydroxyvitamin D3-26,23-lactone each being greater than 90% fraction absorbed.
    [Show full text]
  • Drug Interactions with Smoke and Smoking Cessation Medications
    Drug Interactions with Smoke and Smoking Cessation Medications Paul Oh MD MSc FRCPC FACP Medical Director, Toronto Rehab Assistant Professor, Division of Clinical Pharmacology, University of Toronto Disclosures • Advisory Boards – Amgen, AstraZeneca, BMS, Janssen, Novartis, Pfizer, Sanofi • Research Funding – Heart & Stroke, CIHR • Professional Affiliations: – CACR, CCN, CDA Objectives • review pharmacokinetic principles – what is the disposition of a medication once ingested? • highlight the role of the drug metabolism cytochrome P450 system as a particular site for many important drug interactions • Case based discussion of common interactions – drug-drug (SCT) and drug-smoke Cased Based Questions 1. What is a “CYP” and what does it do? 2. How can a sinus infection make you pass out? 3. Why is this workout so painful? 4. How do cigarettes and coffee go together? 5. Why is quitting possibly hazardous to your drug health? 6. What makes someone with heart disease and depression slow down? Ingestion First-Pass Metabolism Gut Lumen Gut Wall Liver Fraction Fraction Absorbed Metabolized Portal Circulation Metabolism Metabolism Drug Metabolism in the Liver SYSTEMIC LIVER CIRCULATION Eliminated unchanged by the kidneys To the kidneys for PORTAL VEIN elimination Drug Metabolism in the Liver SYSTEMIC LIVER CIRCULATION Eliminated unchanged by the kidneys P-450 OH Phase I metabolism Phase II metabolism Glucuronide OH Phase II metabolism Sulfate To the kidneys for PORTAL VEIN elimination Hepatocytes Cytochrome P450 Overview of Pharmacology Concepts Cytochrome P450 System • Nomenclature: e.g., CYP3A4 – "CYP" = cytochrome P450 protein abbreviation – family; subfamily; isoform • The most important isoforms are CYP3A4, CYP2D6, CYP1A2 – anticipate drug interactions if prescribing drugs using these enzymes.
    [Show full text]