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Clinical Pharmacokinetics of Cannabinoids and Potential Drug-Drug Interactions

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Cannabinoids and Sleep

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1297))

Abstract

Over the past few years, considerable attention has focused on cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the two major constituents of Cannabis sativa, mainly due to the promising potential medical uses they have shown. However, more information on the fate of these cannabinoids in human subjects is still needed and there is limited research on the pharmacokinetic drug-drug interactions that can occur in the clinical setting and their prevalence. As the use of cannabinoids is substantially increasing for many indications and they are not the first-line therapy in any treatment, health care professionals must be aware of drug-drug interactions during their use as serious adverse events can happen related with toxic or ineffective outcomes. The present chapter overview summarizes our current knowledge on the pharmacokinetics and metabolic fate of CBD and THC in humans and discusses relevant drug-drug interactions, giving a plausible explanation to facilitate further research in the area.

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References

  • Abrams DI, Vizoso HP, Shade SB, Jay C, Kelly ME, Benowitz ML (2007) Vaporization as a smokeless cannabis delivery system: a pilot study. Clin Pharmacol Ther 82(5):572–578

    Article  CAS  PubMed  Google Scholar 

  • Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillespie H, Hollister L (1986) Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev 38(1):21–43

    CAS  PubMed  Google Scholar 

  • Agurell S, Leander K (1971) Stability, transfer and absorption of cannabinoid constituents of cannabis (hashish) during smoking. Acta Pharm Suec 8(4):391–402

    CAS  PubMed  Google Scholar 

  • Aizpurua-Olaizola O, Soydaner U, Ozturk E, Schibano D, Simsir Y, Navarro P, Etxebarria N, Usobiaga A (2016) Evolution of the cannabinoid and Terpene content during the growth of Cannabis sativa plants from different Chemotypes. J Nat Prod 79(2):324–331

    Article  CAS  PubMed  Google Scholar 

  • Al Saabi A, Allorge D, Sauvage FL, Tournel G, Gaulier JM, Marquet P, Picard N (2013) Involvement of UDPglucuronosyltransferases UGT1A9 and UGT2B7 in ethanol glucuronidation, and interactions with common drugs of abuse. Drug Metab Dispos 41(3):568–574

    Article  PubMed  CAS  Google Scholar 

  • Anderson GD, Miller JW (2002) Benzodiazepines: chemistry, biotransformation, and pharmacokinetics. In: Levy RH, Mattson RH, Meldru BS et al (eds) Antiepileptic drugs, 5th edn. Lippincott Williams& Wilkins, Philadelphia, PA, pp 187–205

    Google Scholar 

  • Andre CM, Hausman JF, Guerriero G (2016) Cannabis sativa: the Plant of the Thousand and one Molecules. Front Plant Sci 7:19. https://doi.org/10.3389/fpls.2016.00019

    Article  PubMed  PubMed Central  Google Scholar 

  • Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G (2008) Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 133(6):160S–198S

    Article  CAS  PubMed  Google Scholar 

  • Atsmon J, Cherniakov I, Izgelov D, Hoffman A, Domb AJ, Deutsch L, Deutsch F, Heffetz D, Sacks H (2018) PTL401, a new formulation based on pro-Nano dispersion technology, improves Oral cannabinoids bioavailability in healthy volunteers. J Pharm Sci 107(5):1423–1429

    Article  CAS  PubMed  Google Scholar 

  • Atsmon J, Heffetz D, Deutsch L, Deutsch F, Sacks H (2018) Single-dose pharmacokinetics of Oral Cannabidiol following administration of PTL101: a new formulation based on gelatin matrix pellets technology. Clin Pharmacol Drug Dev 7(7):751–758

    Article  CAS  PubMed  Google Scholar 

  • Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF (2002) Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. J Pharmacol Exp Ther 302(2):645–650

    Article  CAS  PubMed  Google Scholar 

  • Boffito M, Dickinson L, Hill A, Back D, Moyle G, Nelson M, Higgs C, Fletcher C, Gazzard B, Pozniak A (2004) Steady-state pharmacokinetics of saquinavir hard-gel/ritonavir/fosamprenavir in HIV-1-infected patients. J Acquir Immune Defic Syndr 37(3):1376–1384

    Article  CAS  PubMed  Google Scholar 

  • Borgelt LM, Franson KL, Nussbaum AM, Wang GS (2013) The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 33(2):195–209

    Article  CAS  PubMed  Google Scholar 

  • Boulton DW, DeVane CL, Liston HL, Markowitz JS (2002) In vitro P-glycoprotein affinity for atypical and conventional antipsychotics. Life Sci 71(2):163–169

    Article  CAS  PubMed  Google Scholar 

  • Brenneisen R (1984) Psychotropic drugs. II. Determination of cannabinoids in Cannabis sativa L. and in cannabis products with high pressure liquid chromatography (HPLC). Pharm Acta Helv 59(9–10):247–259

    CAS  PubMed  Google Scholar 

  • Brenneisen R, Egli A, ElSohly MA, Henn V, Spiess Y (1996) The effect of orally and rectally administered delta 9-tetrahydrocannabinol on spasticity: a pilot study with 2 patients. Int J Clin Pharmacol Ther 34(10):446–452

    CAS  PubMed  Google Scholar 

  • Brzozowska NI, de Tonnerre EJ, Li KM, Wang XS, Boucher AA, Callaghan PD, Kuligowski M, Wong A, Arnold JC (2017) The differential binding of antipsychotic drugs to the ABC transporter P-glycoprotein predicts cannabinoid-antipsychotic drug interactions. Neuropsychopharmacology 42(11):2222–2231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brzozowska NI, Li KM, Wang XS, Booth J, Stuart J, McGregor IS, Arnold JC (2016) ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice. PeerJ 4:e2081

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Carlini EA, Leite JR, Tannhauser M, Berardi AC (1973) Letter: cannabidiol and Cannabis sativa extract protect mice and rats against convulsive agents. J Pharm Pharmacol 25(8):664–665

    Article  CAS  PubMed  Google Scholar 

  • Cherniakov I, Izgelov D, Domb AJ, Hoffman A (2017) The effect of pro Nano Lipospheres (PNL) formulation containing natural absorption enhancers on the oral bioavailability of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in a rat model. Eur J Pharm Sci 109:21–30

    Article  CAS  PubMed  Google Scholar 

  • De Backer B, Debrus B, Lebrun P, Theunis L, Dubois N, Decock L, Verstraete A, Hubert P, Charlier C (2009) Innovative development and validation of an HPLC/DAD method for the qualitative and quantitative determination of major cannabinoids in cannabis plant material. J Chromatogr B Analyt Technol Biomed Life Sci 877(32):4115–4124

    Article  PubMed  CAS  Google Scholar 

  • de Meijer E (2014) The chemical phenotypes (Chemotypes) of cannabis. In: Pertwee RG (ed) Handbook of cannabis. Oxford University Press, Oxford, pp 89–110

    Chapter  Google Scholar 

  • Deshpande A, Mailis-Gagnon A, Zoheiry N, Lakha SF (2015) Efficacy and adverse effects of medical marijuana for chronic non-cancer pain: systematic review of randomized control trials. Can Fam Physician 61(8):e372–e381

    PubMed  PubMed Central  Google Scholar 

  • Dev A, Mundke SS, Pawar PK, Mohanty S (2016) Critical aspects in sublingual route of drug delivery. Pharmaceutical and Biological Evaluations 3(1):42–49

    Google Scholar 

  • Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E, Whalley B, Friedman D (2014) Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55(6):791–802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Devinsky O, Cross JH, Wright S (2017) Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 377(7):699–700

    Article  PubMed  Google Scholar 

  • Devinsky O, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR (2016) Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol 15(3):270–278

    Article  CAS  PubMed  Google Scholar 

  • Di Marzo V (2018) New approaches and challenges to targeting the endocannabinoid system. Nat Rev Drug Discov 17(9):623–639

    Article  PubMed  CAS  Google Scholar 

  • Drewe J, Gutmann H, Fricker G, Török M, Beglinger C, Huwyler J (1999) HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Biochem Pharmacol 57(10):1147–1152

    Article  CAS  PubMed  Google Scholar 

  • Eiraldi R, Sánchez S, Olano I, Vázquez M, Fagiolino P (2004) Study of drug interactions of cyclosporine a in two renal transplant patients. Revista OFIL 14:1):13–1):23

    Google Scholar 

  • Eisenberg E, Ogintz M, Almog S (2014) The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study. J Pain Palliat Care Pharmacother 28(3):216–225

    Article  PubMed  Google Scholar 

  • ElSohly MA, ElSohly HN, Turner CE (1983) Cannabis: new constituents and their pharmacological action. In: Breimer DD, Speise P (eds) Topics in pharmaceutical sciences. Elsevier Science Publishers BV, AMSTERDAM, pp 429–439

    Google Scholar 

  • ElSohly M, Gul W (2014) Constituents of Cannabis sativa. In: Pertwee RG (ed) Handbook of Cannabis. Oxford University Press, Oxford

    Google Scholar 

  • ElSohly MA, Radwan MM, Gul W, Chandra S, Galal A (2017) Phytochemistry of Cannabis sativa L. In: Kinghorn AD, Falk H, Gibbons S, Kobayashi J (eds) Phytocannabinoids: unraveling the Complex Chemistry and Pharmacology of Cannabis sativa. Springer International Publishing, Switzerland, pp 1–36

    Google Scholar 

  • ElSohly MA, Slade D (2005) Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 78:539–548

    Article  CAS  PubMed  Google Scholar 

  • Fankhauser M (2002) History of cannabis in Western medicine. In: Grotenhermen F, Russo E (eds) Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic potential. The Haworth Integrative Healing Press, New York, pp 37–51

    Google Scholar 

  • Fasinu PS, Phillips S, ElSohly MA, Walker LA (2016) Current status and prospects for Cannabidiol preparations as new therapeutic agents. Pharmacotherapy 36(7):781–796

    Article  PubMed  Google Scholar 

  • Feinshtein V, Erez O, Ben-Zvi Z, Erez M, Eshkoli T, Sheizaf B, Sheiner E, Huleihel M, Holcberg G (2013) Cannabidiol changes P-gp and BCRP expression in trophoblast cell lines. PeerJ 1:e153

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Fischedick JT (2017) Identification of Terpenoid Chemotypes among high (−)-trans-Δ9- Tetrahydrocannabinol-producing Cannabis sativa L. cultivars. Cannabis Cannabinoid Res 2(1):34–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flemming T, Muntendam R, Steup C, Kayser O (2007) Chemistry and biological activity of Tetrahydrocannabinol and its derivatives. Top Heterocycl Chem 10:1–42

    Article  CAS  Google Scholar 

  • Flockhart DA (2007) Drug interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine

    Google Scholar 

  • Flores-Sanchez IJ, Verpoorte R (2008) Secondary metabolism in cannabis. Phytochem Rev 7(3):615–639

    Article  CAS  Google Scholar 

  • Fromm MF (2002) The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans. Adv Drug Deliv Rev 54(10):1295–1310

    Article  CAS  PubMed  Google Scholar 

  • Fromm MF (2003) Importance of P-glycoprotein for drug disposition in humans. Eur J Clin Investig 33(Suppl 2):6–9

    Article  CAS  Google Scholar 

  • Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP, UAB CBD Program (2017) Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia 58(9):1586–1592

    Article  CAS  PubMed  Google Scholar 

  • Geffrey AL, Pollack SF, Bruno PL, Thiele EA (2015) Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia 56(8):1246–1251

    Article  CAS  PubMed  Google Scholar 

  • Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, Altman RB, Klein TE (2013) Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics 23(4):236–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giarratano M, Standley K, Benbadis SR (2012) Clobazam for treatment of epilepsy. Expert Opin Pharmacother 13(2):227–233

    Article  CAS  PubMed  Google Scholar 

  • Gieringer D (2001) Cannabis vaporization: a promising strategy for smoke harm reduction. J Cannabis Ther 1:153–170

    Article  Google Scholar 

  • Gieringer D, St Laurent J, Goodrich S (2004) Cannabis vaporizer combines efficient delivery of THC with effective suppression of pyrolytic compounds. J Cannabis Ther 4(1):7–27

    Article  CAS  Google Scholar 

  • Grant KS, Petroff R, Isoherranen N, Stella N, Burbacher TM (2018) Cannabis use during pregnancy: pharmacokinetics and effects on child development. Pharmacol Ther 182:133–151

    Article  CAS  PubMed  Google Scholar 

  • Grayson L, Vines B, Nichol K, Szaflarski JP, Program UABCBD (2017) An interaction between warfarin and cannabidiol, a case report. Epilepsy Behav Case Rep 9:10–11

    Article  PubMed  PubMed Central  Google Scholar 

  • Greenblatt DJ, Zhao Y, Venkatakrishnan K, Duan SX, Harmatz JS, Parent SJ, Court MH, von Moltke LL (2011) Mechanism of cytochrome P450-3A inhibition by ketoconazole. J Pharm Pharmacol 63(2):214–221

    Article  CAS  PubMed  Google Scholar 

  • Grotenhermen F (2003) Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet 42(4):327–360

    Article  CAS  PubMed  Google Scholar 

  • Grotenhermen F (2007) The toxicology of cannabis and cannabis prohibition. Chem Biodivers 4(8):1744–1769

    Article  CAS  PubMed  Google Scholar 

  • Hawksworth G, McArdle K (2004) Metabolism and pharmacokinetics of cannabinoids. In: Guy GW, Whittle BA, Robson PJ (eds) The medicinal uses of cannabis and cannabinoids. London, Pharmaceutical Press, pp 205–228

    Google Scholar 

  • Hazekamp A, Ruhaak R, Zuurman L, van Gerven J, Verpoorte R (2006) Evaluation of a vaporizing device (volcano) for the pulmonary administration of tetrahydrocannabinol. J Pharm Sci 95(6):1308–1317

    Article  CAS  PubMed  Google Scholar 

  • Hillig KW (2005) Genetic evidence for speciation in cannabis (Cannabaceae). Genet Resour Crop Evol 52(2):161–180

    Article  CAS  Google Scholar 

  • Hillig KW, Mahlberg PG (2004) A chemotaxonomic analysis of cannabinoid variation in cannabis (Cannabaceae). Am J Bot 91(6):966–975

    Article  CAS  PubMed  Google Scholar 

  • Holthoewer D, Hiemke C, Schmitt U (2010) Induction of drug transporters alters disposition of Risperidone - a study in mice. Pharmaceutics 2(2):258–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holtzman CW, Wiggins BS, Spinler SA (2006) Role of P-glycoprotein in statin drug interactions. Pharmacotherapy 26(11):1601–1607

    Article  CAS  PubMed  Google Scholar 

  • Huestis MA (2007) Human cannabinoid pharmacokinetics. Chem Biodivers 4(8):1770–1804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hunt CA, Jones RT (1980) Tolerance and disposition of tetrahydrocannabinol in man. J Pharmacol Exp Ther 215(1):35–44

    CAS  PubMed  Google Scholar 

  • Jiang R, Yamaori S, Okamoto Y, Yamamoto I, Watanabe K (2013) Cannabidiol is a potent inhibitor of the catalytic acitivity of cytochrome P450 2C19. Drug Metab Pharmacokinet 28(4):332–338

    Article  CAS  PubMed  Google Scholar 

  • Jiang R, Yamaori S, Takeda S, Yamamoto I, Watanabe K (2011) Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci 89(5–6):165–170

    Article  CAS  PubMed  Google Scholar 

  • Johansson E, Halldin MM, Agurell S, Hollister LE, Gillespie HK (1989) Terminal elimination plasma half-life of delta 1-tetrahydrocannabinol (delta 1-THC) in heavy users of marijuana. Eur J Clin Pharmacol 37(3):273–277

    Article  CAS  PubMed  Google Scholar 

  • Karschner EL, Darwin WD, Goodwin RS, Wright S, Huestis MA (2011) Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration. Clin Chem 57(1):66–75

    Article  CAS  PubMed  Google Scholar 

  • Kerbrat AF, JC FP, Ronzière T, Vannier S, Carsin-Nicol B, Lavoué S, Vérin M, Gauvrit JI, Le Tulzo Y, Edan G (2016) Acute neurologic disorder from an inhibitor of fatty acid amide hydrolase. N Engl J Med 375(18):1717–1725

    Article  CAS  PubMed  Google Scholar 

  • Klausner HA, Wilcox HG, Dingell JV (1975) The use of zonal ultracentrifugation in the investigation of the binding of delta9-tetrahydrocannabinol by plasma lipoproteins. Drug Metab Dispos 3(4):314–319

    CAS  PubMed  Google Scholar 

  • Kosel BW, Aweeka FT, Benowitz NL, Shade SB, Hilton JF, Lizak PS, Abrams DI (2002) The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir. AIDS 16(4):543–550

    Article  CAS  PubMed  Google Scholar 

  • Krishna DR, Klotz U (1994) Extrahepatic metabolism of drugs in humans. Clin Pharmacokinet 26(2):144–160

    Article  CAS  PubMed  Google Scholar 

  • Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshé SL, Perucca E, Wiebe S, French J (2010) Definition of drug resistant epilepsy: consensus proposal of the ad hoc task force of the ILAE commission on therapeutic strategies. Epilepsia 51(6):1069–1077

    Article  CAS  PubMed  Google Scholar 

  • Kwan P, Brodie MJ (2000) Early identification of refractory epilepsy. N Engl J Med 34(5):314–319

    Article  Google Scholar 

  • Lanz C, Mattsson J, Soydaner U, Brenneisen R (2016) Medicinal cannabis: in vitro validation of vaporizers for the smoke-free inhalation of cannabis. PLoS One 11(1):e0147286

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lemberger L, Tamarkin NR, Axelrod J, Kopin IJ (1971) Delta-9-tetrahydrocannabinol: metabolism and disposition in long-term marihuana smokers. Science 173(991):72–74

    Article  CAS  PubMed  Google Scholar 

  • Lewis MA, Russo EB, Smith KM (2018) Pharmacological foundations of cannabis Chemovars. Planta Med 84(04):225–233

    Article  CAS  PubMed  Google Scholar 

  • Loscher W (1999) Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. Prog Neurobiol 58(1):31–59

    Article  CAS  PubMed  Google Scholar 

  • Lown KS, Mayo RR, Leichtman AB, Hsiao HL, Turgeon DK, Schmiedlin-Ren P, Brown MB, Guo W, Rossi SJ, Benet LZ, Watkins PB (1997) Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther 62(3):248–260

    Article  CAS  PubMed  Google Scholar 

  • Mahatthanatrakul W, Nontaput T, Ridtitid W, Wongnawa M, Sunbhanich M (2007) Rifampin, a cytochrome P450 3A inducer, decreases plasma concentrations of antipsychotic risperidone in healthy volunteers. J Clin Pharm Ther 32(2):161–167

    Article  CAS  PubMed  Google Scholar 

  • Maldonado C, Guevara N, Queijo C, González R, Fagiolino P, Vázquez M (2016) Carnitine and/or acetylcarnitine deficiency as a cause of higher levels of ammonia. Biomed Res Int 2016:1–8

    Article  CAS  Google Scholar 

  • Mattes RD, Shaw LM, Edling-Owens J, Engelman K, Elsohly MA (1993) Bypassing the first-pass effect for the therapeutic use of cannabinoids. Pharmacol Biochem Behav 44(3):745–747

    Article  CAS  PubMed  Google Scholar 

  • Mazur A, Lichti CF, Prather PL, Zielinska AK, Bratton SM, Gallus-Zawada A, Finel M, Miller GP, Radomińska-Pandya A, Moran JH (2009) Characterization of human hepatic and extrahepatic UDP-glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids. Drug Metab Dispos 37(7):1496–1504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meng H, Johnston B, Englesakis M, Moulin DE, Bhatia A (2017) Selective cannabinoids for chronic neuropathic pain: a systematic review and meta-analysis. Anesth Analg 125(5):1638–1652

    Article  CAS  PubMed  Google Scholar 

  • Nakanishi H, Yonezawa A, Matsubara K, Yano I (2013) Impact of P-glycoprotein and breast cancer resistance protein on the brain distribution of antiepileptic drugs in knockout mouse models. Eur J Pharmacol 710(1–3):20–28

    Article  CAS  PubMed  Google Scholar 

  • Namazi S, Sh P, Borhani-Haghighi A, Roosta S (2014) Incidence of potential drug-drug interaction and related factors in hospitalized neurological patients in two Iranian teaching hospitals. Iran J Med Sci 39(6):515–521

    PubMed  PubMed Central  Google Scholar 

  • Navarro G, Morales P, Rodríguez-Cueto C, Fernández-Ruiz J, Jagerovic N, Franco R (2016) Targeting cannabinoid CB2 receptors in the central nervous system. Medicinal chemistry approaches with focus on neurodegenerative disorders. Front Neurosci 10:406. https://doi.org/10.3389/fnins.2016.00406

    Article  PubMed  PubMed Central  Google Scholar 

  • Neuvonen PJ, Niemi M, Backman JT (2006) Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 80(6):565–581

    Article  CAS  PubMed  Google Scholar 

  • Nugent SM, Morasco BJ, O'Neil ME, Freeman M, Low A, Kondo K, Elven C, Zakher B, Motu'apuaka M, Paynter R, Kansagara D (2017) The effects of cannabis among adults with chronic pain and an overview of general harms: a systematic review. Ann Intern Med 167(5):319–331

    Article  PubMed  Google Scholar 

  • O’Connell BK, Gloss D, Devinsky O (2017) Cannabinoids in treatment-resistant epilepsy: a review. Epilepsy Behav 70(Pt B):341–348

    Article  PubMed  Google Scholar 

  • Oberbarnscheidt T, Miller NS (2017) Pharmacology of marijuana. J Addict Res Ther S11:012

    Article  Google Scholar 

  • Ohlsson A, Agurell S, Londgren JE, Gillespie HK, Hollister LE (1985) In: Barnett G, Chiang CN (eds) Pharmacokinetics and pharmacodynamics of psychoactive drugs. Mosby Yearbook, St. Louis, p 75

    Google Scholar 

  • Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK (1980) Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther 28(3):409–416

    Article  CAS  PubMed  Google Scholar 

  • Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK (1982) Single dose kinetics of deuterium labelled delta 1-tetrahydrocannabinol in heavy and light cannabis users. Biomed Environ Mass Spectrom 9(1):6–10

    Article  CAS  Google Scholar 

  • Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC (2006) The human intestinal cytochrome P450 “pie”. Drug Metab Dispos 34(5):880–886

    Article  CAS  PubMed  Google Scholar 

  • Pengo V, Pegoraro C, Cucchini U, Iliceto S (2006) Worldwide management of oral anticoagulant therapy: the ISAM study. J Thromb Thrombolysis 21(1):73–77

    Article  PubMed  Google Scholar 

  • Perez-Reyes M, Di Guiseppi S, Davis KH, Schindler VH, Cook CE (1982) Comparison of effects of marihuana cigarettes to three different potencies. Clin Pharmacol Ther 31(5):617–624

    Article  CAS  PubMed  Google Scholar 

  • Perucca E (2017) Cannabinoids in the treatment of epilepsy: hard evidence at last? J Epilepsy Res 7(2):61–76

    Article  PubMed  PubMed Central  Google Scholar 

  • Pollio A (2016) The name of cannabis: a short guide for nonbotanists. Cannabis Cannabinoid Res 1(1):234–238

    Article  PubMed  PubMed Central  Google Scholar 

  • Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, McQuade R, Wright S, Fallon MT (2012) Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded dose trial. J Pain 13(5):438–449

    Article  CAS  PubMed  Google Scholar 

  • Potter DJ (2014) Cannabis horticulture. In: Pertwee RG (ed) Handbook of cannabis. Oxford University Press, Oxford, pp 65–88

    Chapter  Google Scholar 

  • Radwan MM, ElSohly MA, El-Alfy AT, Ahmed SA, Slade D, Husni AS, Manly SP, Wilson L, Seale S, Cutler SJ, Ross SA (2015) Isolation and pharmacological evaluation of minor cannabinoids from high-potency Cannabis sativa. J Nat Prod 78(6):1271–1276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenberg EC, Patra PH, Whalley BJ (2017) Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. Epilepsy Behav 70(Pt B):319–327

    Article  PubMed  PubMed Central  Google Scholar 

  • Russo EB (2007) History of cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers 4(8):1614–1648

    Article  CAS  PubMed  Google Scholar 

  • Sachse-Seeboth C, Pfeil J, Sehrt D, Meineke I, Tzvetkov M, Bruns E, Poser W, Vormfelde SV, Brockmöller J (2009) Interindividual variation in the pharmacokinetics of delta9-tetrahydrocannabinol as related to genetic polymorphisms in CYP2C9. Clin Pharmacol Ther 85(3):273–276

    Article  CAS  PubMed  Google Scholar 

  • Schachter M (2005) Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol 19(1):117–125

    Article  CAS  PubMed  Google Scholar 

  • Schmitt U, Holthoewer D, Mueller M, Hiemke C (2016) Induction of P-glycoprotein reduces the in vivo activity of Risperidone in mice. SM J Neurol Disord Stroke 2(2):1011

    Google Scholar 

  • Shirasaka Y, Sager JE, Lutz JD, Davis C, Isoherranen N (2013) Inhibition of CYP2C19 and CYP3A4 by omeprazole metabolites and their contribution to drug-drug interactions. Drug Metab Dispos 41(7):1414–1424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siemes H, Nau H, Schultze K, Wittfoht W, Drews E, Penzien J, Seidel U (1993) Valproate (VPA) metabolites in various clinical conditions of probable VPA-associated hepatotoxicity. Epilepsia 34(2):332–346

    Article  CAS  PubMed  Google Scholar 

  • Small E (2017) Classification of Cannabis sativa L. in Relation to Agricultural, Biotechnological, Medical and Recreational Utilization. In: Chandra S, Lata H, MA ES (eds) Cannabis sativa L. – Botany and Biotechnology. Springer International Publishing, Switzerland, pp 1–62

    Google Scholar 

  • Spiro AS, Wong A, Boucher AA, Arnold JC (2012) Enhanced brain disposition and effects of D9-Tetrahydrocannabinol in P-glycoprotein and breast cancer resistance protein knockout mice. PLoS One 7(4):e35937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stevens AJ, Higgins MD (2017) A systematic review of the analgesic efficacy of cannabinoid medications in the management of acute pain. Acta Anaesthesiol Scand 61(3):268–280

    Article  CAS  PubMed  Google Scholar 

  • Stinchcomb AL, Valiveti S, Hammell DC, Ramsey DR (2004) Human skin permeation of Delta8-tetrahydrocannabinol, cannabidiol and cannabinol. J Pharm Pharmacol 56(3):291–297

    Article  CAS  PubMed  Google Scholar 

  • Stott C, Wright S, Wilbraham D, Guy G (2013) A phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of rifampicin, ketoconazole, and omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers. Springerplus 2(1):236

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stout SM, Cimino NM (2014) Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev 46(1):86–95

    Article  CAS  PubMed  Google Scholar 

  • Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K, GWPCARE4 Study Group (2018) Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 391(10125):1085–1096

    Article  CAS  PubMed  Google Scholar 

  • Thomas BF, ElSohly MA (2016) The analytical chemistry of cannabis. Elsevier, Amsterdam. ISBN 9780128046463

    Google Scholar 

  • Thummel KE (2007) Gut instincts: CYP3A4 and intestinal drug metabolism. J Clin Invest 117(11):3173–3176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Todd SM, Arnold JC (2016) Neural correlates of cannabidiol and Delta9tetrahydrocannabinol interactions in mice: implications for medical cannabis. Br J Pharmacol 173(1):53–65

    Article  CAS  PubMed  Google Scholar 

  • Ujváry I, Hanuš L (2016) Human metabolites of Cannabidiol: a review on their formation, biological activity, and relevance in therapy. Cannabis Cannabinoid Res 1(1):90–101

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • van Esbroeck ACM, Janssen APA, Cognetta AB, Ogasawara D, Shpak G, van der Kroeg M, Kantae V, Baggelaar MP, de Vrij FMS, Deng H, Allarà M, Fezza F, Lin Z, van der Wel T, Soethoudt M, Mock ED, den Dulk H, Baak IL, Florea BI, Hendriks G, De Petrocellis L, Overkleeft HS, Hankemeier T, De Zeeuw CI, Di Marzo V, Maccarrone M, Cravatt BF, Kushner SA, van der Stelt M (2017) Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10–2474. Science 356(6342):1084–1087

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • van Hoogdalem E, de Boer AG, Breimer DD (1991) Pharmacokinetics of rectal drug administration, part I. general considerations and clinical applications of centrally acting drugs. Clin Pharmacokinet 21(1):11–26

    Article  PubMed  Google Scholar 

  • Vázquez M, Fagiolino P, Maldonado C, Olmos I, Ibarra M, Alvariza S, Guevara N, Magallanes L, Olano I (2014) Hyperammonemia associated with valproic acid concentrations. Biomed Res Int 2014:1–8

    Article  CAS  Google Scholar 

  • Vázquez M, Fagiolino P, Mariño EL (2013) Concentration-dependent mechanisms of adverse drug reactions in epilepsy. Curr Pharm Des 19(38):6802–6808

    Article  PubMed  CAS  Google Scholar 

  • Wacher VJ, Silverman JA, Zhang Y, Benet LZ (1998) Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci 87(11):1322–1330

    Article  CAS  PubMed  Google Scholar 

  • Wahlqvist M, Nilsson IM, Sandberg F, Agurell S (1970) Binding of delta-1-tetrahydrocannabinol to human plasma proteins. Biochem Pharmacol 19(9):2579–2584

    Article  CAS  PubMed  Google Scholar 

  • Walzer M, Bekersky I, Blum RA, Tolbert D (2012) Pharmacokinetic drug interactions between clobazam and drugs metabolized by cytochrome P450 isoenzymes. Pharmacotherapy 32(4):340–353

    Article  CAS  PubMed  Google Scholar 

  • Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A, Bennett GJ, Collet JP (2010) Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 182(14):E694–E701

    Article  PubMed  PubMed Central  Google Scholar 

  • Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J (2015) Cannabinoids for medical use: a systematic review and meta-analysis. JAMA 313(24):2456–2473

    Article  CAS  PubMed  Google Scholar 

  • Widman M, Agurell S, Ehrnebo M, Jones G (1974) Binding of (+) and (−)-Δ1-tetrahydrocannabinols and (−)-7-hydroxy-Δ1-tetrahydrocannabinol to blood cells and plasma proteins in man. J Pharm Pharmacol 26(11):914–916

    Article  CAS  PubMed  Google Scholar 

  • Wills S (1998) Cannabis use and abuse by man: an historical perspective. In: Brown DT (ed) Cannabis: the genus cannabis. Harwood Academic Publishers, Amsterdam, pp 1–27

    Google Scholar 

  • Yamamoto I, Watanabe K, Matsunaga T, Kimura T, Funahashi T, Yoshimura H (2003) Pharmacology and toxicology of major constituents of marijuana - on the metabolic activation of cannabinoids and its mechanism. J Toxicol Toxin Rev 22(4):577–589

    Article  CAS  Google Scholar 

  • Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K (2011) Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sci 88(15–16):730–736

    Article  CAS  PubMed  Google Scholar 

  • Yamaori S, Koeda K, Kushihara M, Hada Y, Yamamoto I, Watanabe K (2012) Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity. Drug Metab Pharmacokinet 27(3):294–300

    Article  CAS  PubMed  Google Scholar 

  • Yamaori S, Okamoto Y, Yamamoto I, Watanabe K (2011) Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab Dispos 39(11):2049–2056

    Article  CAS  PubMed  Google Scholar 

  • Zendulka O, Dovrtělová G, Nosková K, Turjap M, Šulcová A, Hanuš L, Juřica J (2016) Cannabinoids and cytochrome P450 interactions. Curr Drug Metab 17(3):206–226

    Article  CAS  PubMed  Google Scholar 

  • Zhu HJ, Wang JS, Markowitz JS, Donovan JL, Gibson BB, Gefroh HA, Devane CL (2006) Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana. J Pharmacol Exp Ther 317(2):850–857

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Pharmaceutical Sciences Department, Faculty of Chemistry, University of the Republic, Montevideo, Uruguay

    Marta Vázquez, Cecilia Maldonado & Pietro Fagiolino

  2. Pharmacognosy & Natural Products Laboratory, Organic Chemistry Department, Faculty of Chemistry, University of the Republic, Montevideo, Uruguay

    Carlos García-Carnelli

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  1. Marta Vázquez
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  2. Carlos García-Carnelli
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  3. Cecilia Maldonado
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  4. Pietro Fagiolino
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Correspondence to Marta Vázquez .

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  1. School of Medicine, University of the Republic, Montevideo, Uruguay

    Jaime M. Monti

  2. Somnogen Canada Inc., Toronto, ON, Canada

    S. R. Pandi-Perumal

  3. División Ciencias de la Salud, Universidad Anáhuac Mayab, Merida, Mexico

    Eric Murillo-Rodríguez

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Vázquez, M., García-Carnelli, C., Maldonado, C., Fagiolino, P. (2021). Clinical Pharmacokinetics of Cannabinoids and Potential Drug-Drug Interactions. In: Monti, J.M., Pandi-Perumal, S.R., Murillo-Rodríguez, E. (eds) Cannabinoids and Sleep. Advances in Experimental Medicine and Biology, vol 1297. Springer, Cham. https://doi.org/10.1007/978-3-030-61663-2_3

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