Impact of Inflammation on Midazolam Metabolism in Severe COVID-19 Patients.
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
11 2022
11 2022
Historique:
received:
29
11
2021
accepted:
12
06
2022
pubmed:
2
7
2022
medline:
25
10
2022
entrez:
1
7
2022
Statut:
ppublish
Résumé
Midazolam is a benzodiazepine frequently used for sedation in patients hospitalized in the intensive care unit (ICU) for coronavirus disease 2019 (COVID-19). This drug is primarily metabolized by cytochrome P450 3A (CYP3A) isoenzymes. Several studies have suggested that inflammation, frequently observed in these patients, could modulate CYP3A activity. The objective of this work was to study the impact of inflammation on midazolam pharmacokinetics in patients with COVID-19. Forty-eight patients hospitalized in the ICU for COVID-19 and treated with midazolam administered by continuous infusion were included in this study. Midazolam and α-hydroxymidazolam concentrations were measured and patient data, including the use of CYP3A inhibitors, were collected. Total and unbound concentrations of midazolam and α-hydroxymidazolam were measured in plasma using a validated liquid-chromatography coupled with mass spectrometry method. Inflammatory condition was evaluated by C-reactive protein (CRP) level measurement. Both drug concentrations and CRP measurements were performed on 354 plasma samples. CRP elevation was significantly associated with the α-hydroxymidazolam/midazolam plasma ratio decrease, whether for the unbound fraction or for the total fraction. Conversely, inflammation was not associated with protein binding modifications. Logically, α-hydroxymidazolam/midazolam plasma ratio was significantly reduced when patients were treated with CYP3A inhibitors. In this study, we showed that inflammation probably reduces the metabolism of midazolam by CYP3A. These results suggest that molecules with narrow therapeutic margins and metabolized by CYP3A should be administrated with care in case of massive inflammatory situations.
Identifiants
pubmed: 35776074
doi: 10.1002/cpt.2698
pmc: PMC9350233
doi:
Substances chimiques
Midazolam
R60L0SM5BC
Cytochrome P-450 CYP3A
EC 1.14.14.1
Isoenzymes
0
C-Reactive Protein
9007-41-4
Cytochrome P-450 CYP3A Inhibitors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1033-1039Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics.
Références
Kupietzky, A. & Houpt, M.I. Midazolam: a review of its use for conscious sedation of children. Pediatr. Dent. 15, 237-241 (1993).
Wandel, C., Böcker, R., Böhrer, H., Browne, A., Rügheimer, E. & Martin, E. Midazolam is metabolized by at least three different cytochrome P450 enzymes. Br. J. Anaesth. 73, 658-661 (1994).
Pieri, L. Preclinical pharmacology of midazolam. Br. J. Clin. Pharmacol. 16, 17S-27S (1983).
Mandona, J.W., Tuk, B., van Steveninck, A.L., Breimer, D.D., Cohen, A.F. & Danhof, M. Pharmacokinetic-pharmacodynamic modeling of the central nervous system effects of midazolam and its main metabolite α-hydroxymidazolam in healthy volunteers. Clin. Pharmacol. Ther. 51, 715-728 (1992).
Heizmann, P., Eckert, M. & Ziegler, W. Pharmacokinetics and bioavailability of midazolam in man. Br. J. Clin. Pharmacol. 16, 43S-49S (1983).
Gustine, J.N. & Jones, D. Immunopathology of hyperinflammation in COVID-19. Am. J. Pathol. 191, 4-17 (2021).
Kadkhoda, K. COVID-19: an immunopathological view. mSphere 5, e00344-20 (2020).
Shah, R.R. & Smith, R.L. Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine. Drug Metab. Dispos. 43, 400-410 (2015).
Gregoire, M. et al. Lopinavir pharmacokinetics in COVID-19 patients. J. Antimicrob. Chemother. 75, 2702-2704 (2020).
Du Bois, D. & Du Bois, E.F. A formula to estimate the approximate surface area if height and weight be known. 1916. Nutrition 303, 312-313 (1989).
Levey AS, Stevens LA, Schmid CH, Iii AFC, Feldman HI, Kusek JW, Eggers P, Coresh J. A new equation to estimate glomerular filtration rate. Ann. Intern. Med. 150, 604-612 (2009).
Illamola, S.M. et al. Determination of total and unbound concentrations of lopinavir in plasma using liquid chromatography-tandem mass spectrometry and ultrafiltration methods. J. Chromatogr. B Analyt. Technol. Biomed Life Sci. 965, 216-223 (2014).
R: the R project for statistical computing <https://www.r-project.org/>
Neely, M.N., Van, G.M.G., Yamada, W.M., Schumitzky, A. & Jelliffe, R.W. Accurate detection of outliers and subpopulations with Pmetrics, a nonparametric and parametric pharmacometric modeling and simulation package for R. Ther. Drug Monit. 34, 467-476 (2012).
Ye, Q., Wang, B. & Mao, J. The pathogenesis and treatment of the ‘cytokine storm’ in COVID-19. J. Infect. 80, 607-613 (2020).
Channappanavar, R. & Perlman, S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin. Immunopathol. 39, 529-539 (2017).
Zhang, Y. et al. Analysis of serum cytokines in patients with severe acute respiratory syndrome. Infect. Immun. 72, 4410-4415 (2004).
Wong, C.K. et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin. Exp. Immunol. 136, 95-103 (2004).
Stanke-Labesque, F., Gautier-Veyret, E., Chhun, S. & Guilhaumou, R. Inflammation is a major regulator of drug metabolizing enzymes and transporters: consequences for the personalization of drug treatment. Pharmacol. Ther. 215, 107627 (2020).
Gautier-Veyret, E. et al. Optimization of voriconazole therapy for treatment of invasive aspergillosis: pharmacogenomics and inflammatory status need to be evaluated. Br. J. Clin. Pharmacol. 87, 2534-2541 (2021).
Gautier-Veyret, E. et al. Inflammation is a potential risk factor of voriconazole overdose in hematological patients. Fundam. Clin. Pharmacol. 33, 232-238 (2018).
Naito, T., Yamada, T., Mino, Y. & Kawakami, J. Impact of inflammation and concomitant glucocorticoid administration on plasma concentration of triazole antifungals in immunocompromised patients. Clin. Chim. Acta 441, 127-132 (2015).
van Wanrooy, M.J. et al. Inflammation is associated with voriconazole trough concentrations. Antimicrob Agents Chemother. 58, 7098-7101 (2014).
Encalada Ventura, M.A. et al. Longitudinal analysis of the effect of inflammation on voriconazole trough concentrations. Antimicrob. Agents Chemother. 60, 2727-2731 (2016).
Bolcato, L. et al. Combined impact of inflammation and pharmacogenomic variants on voriconazole trough concentrations: a meta-analysis of individual data. JCM 10, 2089 (2021).
Schoergenhofer, C., Jilma, B., Stimpfl, T., Karolyi, M. & Zoufaly, A. Pharmacokinetics of lopinavir and ritonavir in patients hospitalized with coronavirus disease 2019 (COVID-19). Ann. Intern. Med. 173, 670-672 (2020).
Cranshaw, T. & Harikumar, T. COVID-19 infection may cause clozapine intoxication: case report and discussion. Schizophr. Bull. 46, 751 (2020).
Halliday, N.J., Dundee, J.W., Collier, P.S., Loughran, P.G. & Harper, K.W. Influence of plasma proteins on the onset of hypnotic action of intravenous midazolam. Anaesthesia 40, 763-766 (1985).
Israili, Z.H. & Dayton, P.G. Human alpha-1-glycoprotein and its interactions with drugs. Drug Metab. Rev. 33, 161-235 (2001).
Soeters, P.B., Wolfe, R.R. & Shenkin, A. Hypoalbuminemia: pathogenesis and clinical significance. J. Parenter. Enteral. Nutr. 43, 181-193 (2019).
Aziz, M., Fatima, R., Lee-Smith, W. & Assaly, R. The association of low serum albumin level with severe COVID-19: a systematic review and meta-analysis. Crit Care 24, 255 (2020).