Importance of cytochrome 3A4 and 2D6-mediated drug-drug interactions in oxycodone consumption among older adults hospitalized for hip fracture: a cross-sectional study.
Cytochrome P450
Drug metabolism
Hip fracture
Hip pain
Inter-individual variability
Oxycodone
Journal
Aging clinical and experimental research
ISSN: 1720-8319
Titre abrégé: Aging Clin Exp Res
Pays: Germany
ID NLM: 101132995
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
received:
05
07
2023
accepted:
18
09
2023
medline:
8
11
2023
pubmed:
20
10
2023
entrez:
20
10
2023
Statut:
ppublish
Résumé
Hip fracture is a common injury and represents a major health problem with an increasing incidence. In older adults, opioids such as oxycodone are often preferred to other analgesics such as tramadol because of a lower risk of delirium. Different parameters, such as inhibition of cytochrome P450 (CYP450) 2D6 and/or 3A4, can potentially lead to pharmacokinetic variations of oxycodone representing a risk of adverse drugs effects or lack of drug response. There is a risk of drug-drug interactions involving CYP450 in older adults due to the high prevalence of polypharmacy. This study sought to identify patient characteristics that influence oxycodone administration. A single-center observational study included 355 patients with a hip fracture hospitalized in a geriatric postoperative unit. Composite endpoint based on form, duration, and timing to intake separated patients into three groups: "no oxycodone", "low oxycodone ", and "high oxycodone ". CYP450 interactions were studied based on a composite variable defining the most involved CYP450 pathways between CYP2D6 and CYP3A4. CYP450 interactions with CYP2D6 pathway involved were associated with the risk of "high oxycodone" [odds ratio adjusted on age and the type of hip fracture (OR*) 4.52, 95% confidence interval (CI) 1.39-16.83, p = 0.02)], as well as serum albumin levels (OR* 1.09, 95% CI 1.02-1.17, p = 0.01). Cognitive impairment was negatively associated with the risk of "high oxycodone" (OR* 0.38, 95% CI 0.18-0.77, p = 0.02). This study showed an association between CYP2D6 interactions and higher oxycodone consumption indirectly reflecting the existence of uncontrolled postoperative pain.
Identifiants
pubmed: 37861957
doi: 10.1007/s40520-023-02569-7
pii: 10.1007/s40520-023-02569-7
doi:
Substances chimiques
Oxycodone
CD35PMG570
Cytochrome P-450 CYP2D6
EC 1.14.14.1
Cytochrome P-450 CYP2D6 Inhibitors
0
Analgesics, Opioid
0
Types de publication
Observational Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2471-2481Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
Références
Berry SD, Kiel DP, Colón-Emeric C (2019) Hip Fractures in Older Adults in 2019. JAMA 321:2231–2232. https://doi.org/10.1001/jama.2019.5453
doi: 10.1001/jama.2019.5453
pmcid: 6800121
pubmed: 31074763
Veronese N, Maggi S (2018) Epidemiology and social costs of hip fracture. Injury 49:1458–1460. https://doi.org/10.1016/j.injury.2018.04.015
doi: 10.1016/j.injury.2018.04.015
pubmed: 29699731
Fernandez MA, Griffin XL, Costa ML (2015) Management of hip fracture. Br Med Bull 115:165–172. https://doi.org/10.1093/bmb/ldv036
doi: 10.1093/bmb/ldv036
pubmed: 26311503
Tedesco D, Gibertoni D, Rucci P et al (2018) Impact of rehabilitation on mortality and readmissions after surgery for hip fracture. BMC Health Serv Res 18:701. https://doi.org/10.1186/s12913-018-3523-x
doi: 10.1186/s12913-018-3523-x
pmcid: 6131904
pubmed: 30200950
Seitz DP, Gill SS, Austin PC et al (2016) Rehabilitation of Older Adults with Dementia After Hip Fracture. J Am Geriatr Soc 64:47–54. https://doi.org/10.1111/jgs.13881
doi: 10.1111/jgs.13881
pubmed: 26782851
Swart LM, van der Zanden V, Spies PE et al (2017) The Comparative Risk of Delirium with Different Opioids: A Systematic Review. Drugs Aging 34:437–443. https://doi.org/10.1007/s40266-017-0455-9
doi: 10.1007/s40266-017-0455-9
pmcid: 5427092
pubmed: 28405945
Brouquet A, Cudennec T, Benoist S et al (2010) Impaired mobility, ASA status and administration of tramadol are risk factors for postoperative delirium in patients aged 75 years or more after major abdominal surgery. Ann Surg 251:759–765. https://doi.org/10.1097/SLA.0b013e3181c1cfc9
doi: 10.1097/SLA.0b013e3181c1cfc9
pubmed: 20224380
Barkin RL, Beckerman M, Blum SL et al (2010) Should nonsteroidal anti-inflammatory drugs (NSAIDs) be prescribed to the older adult? Drugs Aging 27:775–789. https://doi.org/10.2165/11539430-000000000-00000
doi: 10.2165/11539430-000000000-00000
pubmed: 20883058
Gabriel RA, Swisher MW, Sztain JF et al (2019) State of the art opioid-sparing strategies for post-operative pain in adult surgical patients. Expert Opin Pharmacother 20:949–961. https://doi.org/10.1080/14656566.2019.1583743
doi: 10.1080/14656566.2019.1583743
pubmed: 30810425
Kokki H, Kokki M, Sjövall S (2012) Oxycodone for the treatment of postoperative pain. Expert Opin Pharmacother 13:1045–1058. https://doi.org/10.1517/14656566.2012.677823
doi: 10.1517/14656566.2012.677823
pubmed: 22519769
International Narcotics Control Board, United Nations. Available online: https://www.incb.org/incb/en/publications/annual-reports/annual-report-2020.html (accessed on 24 October 2022).
Huddart R, Clarke M, Altman RB et al (2018) PharmGKB summary: oxycodone pathway, pharmacokinetics. Pharmacogenet Genomics 28:230–237. https://doi.org/10.1097/FPC.0000000000000351
doi: 10.1097/FPC.0000000000000351
pmcid: 6602093
pubmed: 30222708
Saari TI, Ihmsen H, Neuvonen PJ et al (2012) Oxycodone clearance is markedly reduced with advancing age: a population pharmacokinetic study. Br J Anaesth 108:491–498. https://doi.org/10.1093/bja/aer395
doi: 10.1093/bja/aer395
pubmed: 22201184
Liukas A, Kuusniemi K, Aantaa R et al (2008) Plasma concentrations of oral oxycodone are greatly increased in the elderly. Clin Pharmacol Ther 84:462–467. https://doi.org/10.1038/clpt.2008.64
doi: 10.1038/clpt.2008.64
pubmed: 19238650
Liukas A, Kuusniemi K, Aantaa R et al (2011) Elimination of intravenous oxycodone in the elderly: a pharmacokinetic study in postoperative orthopaedic patients of different age groups. Drugs Aging 28:41–50. https://doi.org/10.2165/11586140-000000000-00000
doi: 10.2165/11586140-000000000-00000
pubmed: 21174486
Lalovic B, Kharasch E, Hoffer C et al (2006) Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther 79:461–479. https://doi.org/10.1016/j.clpt.2006.01.009
doi: 10.1016/j.clpt.2006.01.009
pubmed: 16678548
Lalovic B, Phillips B, Risler LL et al (2004) Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos 32:447–454. https://doi.org/10.1124/dmd.32.4.447
doi: 10.1124/dmd.32.4.447
pubmed: 15039299
Romand S, Spaggiari D, Marsousi N et al (2017) Characterization of oxycodone in vitro metabolism by human cytochromes P450 and UDP-glucuronosyltransferases. J Pharm Biomed Anal 144:129–137. https://doi.org/10.1016/j.jpba.2016.09.024
doi: 10.1016/j.jpba.2016.09.024
pubmed: 27692933
Liukas A, Hagelberg NM, Kuusniemi K et al (2011) Inhibition of cytochrome P450 3A by clarithromycin uniformly affects the pharmacokinetics and pharmacodynamics of oxycodone in young and elderly volunteers. J Clin Psychopharmacol 31:302–308. https://doi.org/10.1097/JCP.0b013e3182189892
doi: 10.1097/JCP.0b013e3182189892
pubmed: 21508859
Grönlund J, Saari T, Hagelberg N et al (2010) Effect of telithromycin on the pharmacokinetics and pharmacodynamics of oral oxycodone. J Clin Pharmacol 50:101–108. https://doi.org/10.1177/0091270009336444
doi: 10.1177/0091270009336444
pubmed: 19755414
Nieminen TH, Hagelberg NM, Saari TI et al (2010) Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir. Eur J Clin Pharmacol 66:977–985. https://doi.org/10.1007/s00228-010-0879-1
doi: 10.1007/s00228-010-0879-1
pubmed: 20697700
Hagelberg NM, Nieminen TH, Saari TI et al (2009) Voriconazole drastically increases exposure to oral oxycodone. Eur J Clin Pharmacol 65:263–271. https://doi.org/10.1007/s00228-008-0568-5
doi: 10.1007/s00228-008-0568-5
pubmed: 18836708
Saari TI, Grönlund J, Hagelberg NM et al (2010) Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone. Eur J Clin Pharmacol 66:387–397. https://doi.org/10.1007/s00228-009-0775-8
doi: 10.1007/s00228-009-0775-8
pubmed: 20076952
Nieminen TH, Hagelberg NM, Saari TI et al (2009) Rifampin greatly reduces the plasma concentrations of intravenous and oral oxycodone. Anesthesiology 110:1371–1378. https://doi.org/10.1097/ALN.0b013e31819faa54
doi: 10.1097/ALN.0b013e31819faa54
pubmed: 19417618
Lee HK, Lewis LD, Tsongalis GJ et al (2006) Negative urine opioid screening caused by rifampin-mediated induction of oxycodone hepatic metabolism. Clin Chim Acta 367:196–200. https://doi.org/10.1016/j.cca.2005.11.030
doi: 10.1016/j.cca.2005.11.030
pubmed: 16414038
Sakamoto A, Yamashita M, Hori Y et al (2017) Oxycodone Resistance Due to Rifampin Use in an Osteosarcoma Patient with Tuberculosis. Am J Case Rep 18:1130–1134
doi: 10.12659/AJCR.905637
pmcid: 5665608
pubmed: 29061956
Grönlund J, Saari TI, Hagelberg NM et al (2010) Exposure to oral oxycodone is increased by concomitant inhibition of CYP2D6 and 3A4 pathways, but not by inhibition of CYP2D6 alone. Br J Clin Pharmacol 70:78–87. https://doi.org/10.1111/j.1365-2125.2010.03653.x
doi: 10.1111/j.1365-2125.2010.03653.x
pmcid: 2909810
pubmed: 20642550
Kummer O, Hammann F, Moser C et al (2011) Effect of the inhibition of CYP3A4 or CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Eur J Clin Pharmacol 67:63–71. https://doi.org/10.1007/s00228-010-0893-3
doi: 10.1007/s00228-010-0893-3
pubmed: 20857093
Grönlund J, Saari TI, Hagelberg NM et al (2011) Effect of inhibition of cytochrome P450 enzymes 2D6 and 3A4 on the pharmacokinetics of intravenous oxycodone: a randomized, three-phase, crossover, placebo-controlled study. Clin Drug Investig 31:143–153. https://doi.org/10.2165/11539950-000000000-00000
doi: 10.2165/11539950-000000000-00000
pubmed: 21142269
Zanger UM, Schwab M (2013) Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 138:103–141. https://doi.org/10.1016/j.pharmthera.2012.12.007
doi: 10.1016/j.pharmthera.2012.12.007
pubmed: 23333322
van den Anker J, Reed MD, Allegaert K et al (2018) Developmental Changes in Pharmacokinetics and Pharmacodynamics. J Clin Pharmacol 58:S10–S25. https://doi.org/10.1002/jcph.1284
doi: 10.1002/jcph.1284
pubmed: 30248190
Zhao M, Ma J, Li M et al (2021) Cytochrome P450 Enzymes and Drug Metabolism in Humans. Int J Mol Sci 22:12808. https://doi.org/10.3390/ijms222312808
doi: 10.3390/ijms222312808
pmcid: 8657965
pubmed: 34884615
Maher RL, Hanlon J, Hajjar ER (2014) Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf 13:57–65. https://doi.org/10.1517/14740338.2013.827660
doi: 10.1517/14740338.2013.827660
pubmed: 24073682
Collet JP, Thiele H, Barbato E et al (2021) 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 42:1289–1367. https://doi.org/10.1093/eurheartj/ehaa575
doi: 10.1093/eurheartj/ehaa575
pubmed: 32860058
Service de pharmacologie et toxicologie cliniques - Hôpitaux universitaires de Genève. Available online : https://www.hug.ch/sites/interhug/files/structures/pharmacologie_et_toxicologie_cliniques/images/carte_des_cytochromes_2020.pdf (accessed on 13 November 2022).
Food and Drugs Administration. Available online: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers (accessed on 13 November 2022).
Gallo P, De Vincentis A, Pedone C et al (2019) Drug-drug interactions involving CYP3A4 and p-glycoprotein in hospitalized elderly patients. Eur J Intern Med 65:51–57. https://doi.org/10.1016/j.ejim.2019.05.002
doi: 10.1016/j.ejim.2019.05.002
pubmed: 31084979
Hadjistavropoulos T, Herr K, Prkachin KM et al (2014) Pain assessment in elderly adults with dementia. Lancet Neurol 13:1216–1227. https://doi.org/10.1016/S1474-4422(14)70103-6
doi: 10.1016/S1474-4422(14)70103-6
pubmed: 25453461
Silbert B, Evered L, Scott DA et al (2015) Preexisting cognitive impairment is associated with postoperative cognitive dysfunction after hip joint replacement surgery. Anesthesiology 122:1224–1234. https://doi.org/10.1097/ALN.0000000000000671
doi: 10.1097/ALN.0000000000000671
pubmed: 25859906
Dolatowski FC, Frihagen F, Bartels S et al (2019) Screw Fixation Versus Hemiarthroplasty for Nondisplaced Femoral Neck Fractures in Elderly Patients: A Multicenter Randomized Controlled Trial. J Bone Joint Surg Am 101:136–144. https://doi.org/10.2106/JBJS.18.00316
doi: 10.2106/JBJS.18.00316
pubmed: 30653043
Strike SA, Sieber FE, Gottschalk A et al (2013) Role of fracture and repair type on pain and opioid use after hip fracture in the elderly. Geriatr Orthop Surg Rehabil 4:103–108. https://doi.org/10.1177/2151458513518343
doi: 10.1177/2151458513518343
pmcid: 3943362
pubmed: 24600530
Seripa D, Pilotto A, Panza F et al (2010) Pharmacogenetics of cytochrome P450 (CYP) in the elderly. Ageing Res Rev 9:457–474. https://doi.org/10.1016/j.arr.2010.06.001
doi: 10.1016/j.arr.2010.06.001
pubmed: 20601196
Ghoneim MM, O’Hara MW (2016) Depression and postoperative complications: an overview. BMC Surg 16:5. https://doi.org/10.1186/s12893-016-0120-y
doi: 10.1186/s12893-016-0120-y
pmcid: 4736276
pubmed: 26830195