Abstract: Background and Objective: Midazolam is the preferred clinical probe drug for assessing CYP3A activity. We have previously shown substantial intraindividual variability in midazolam absolute bioavailability and clearance in patients with obesity before and after weight loss induced by gastric bypass or a strict diet. The objective was to describe intraindividual variability in absolute bioavailability and clearance of midazolam in healthy individuals without obesity.
Methods: This study included 33 healthy volunteers [28 ± 8 years, 21% males, body mass index (BMI) 23 ± 2.5 kg/m 2 ] subjected to four pharmacokinetic investigations over a 2-month period (weeks 0, 2, 4, and 8). Semi-simultaneous oral (0 h) and intravenous (2 h later) midazolam dosing was used to assess absolute bioavailability and clearance of midazolam.
Results: At baseline, mean absolute bioavailability and clearance were 46 ± 18% and 31 ± 10 L/h, respectively. The mean coefficient of variation (CV, %) for absolute bioavailability and clearance of midazolam was 26 ± 15% and 20 ± 10%, respectively. Approximately one-third had a CV > 30% for absolute bioavailability, while 13% had a CV > 30% for clearance.
Conclusions: On average, intraindividual variability in absolute bioavailability and clearance of midazolam was low to moderate; however, especially absolute bioavailability showed considerable variability in a relatively large proportion of the individuals.
(© 2023. The Author(s).)
References: Saravanakumar A, et al. Physicochemical properties, biotransformation, and transport pathways of established and newly approved medications: a systematic review of the top 200 most prescribed drugs vs. the FDA-approved drugs between 2005 and 2016. Clin Pharmacokinet. 2019;58(10):1281–94. (PMID: 10.1007/s40262-019-00750-8309726946773482)
Paine MF, et al. The human intestinal cytochrome P450 “pie.” Drug Metab Dispos. 2006;34(5):880–6. (PMID: 10.1124/dmd.105.00867216467132)
Achour B, Barber J, Rostami-Hodjegan A. Expression of hepatic drug-metabolizing cytochrome p450 enzymes and their intercorrelations: a meta-analysis. Drug Metab Dispos. 2014;42(8):1349–56. (PMID: 10.1124/dmd.114.05883424879845)
Grangeon A, et al. Determination of CYP450 expression levels in the human small intestine by mass spectrometry-based targeted proteomics. Int J Mol Sci. 2021;22(23):12791. (PMID: 10.3390/ijms222312791348845958657875)
Daly AK. Significance of the minor cytochrome P450 3A isoforms. Clin Pharmacokinet. 2006;45(1):13–31. (PMID: 10.2165/00003088-200645010-0000216430309)
Rendic S, Guengerich FP. Survey of human oxidoreductases and cytochrome p450 enzymes involved in the metabolism of xenobiotic and natural chemicals. Chem Res Toxicol. 2015;28(1):38–42. (PMID: 10.1021/tx500444e25485457)
Kuehl P, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;27(4):383–91. (PMID: 10.1038/8688211279519)
Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103–41. (PMID: 10.1016/j.pharmthera.2012.12.00723333322)
Lenoir C, et al. Influence of inflammation on cytochromes p450 activity in adults: a systematic review of the literature. Front Pharmacol. 2021;12: 733935. (PMID: 10.3389/fphar.2021.733935348673418637893)
Hohmann N, Haefeli WE, Mikus G. CYP3A activity: towards dose adaptation to the individual. Expert Opin Drug Metab Toxicol. 2016;12(5):479–97. (PMID: 10.1517/17425255.2016.116333726950050)
Fuhr U, Jetter A, Kirchheiner J. Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the “cocktail” approach. Clin Pharmacol Ther. 2007;81(2):270–83. (PMID: 10.1038/sj.clpt.610005017259951)
Chung E, et al. Comparison of midazolam and simvastatin as cytochrome P450 3A probes. Clin Pharmacol Ther. 2006;79(4):350–61. (PMID: 10.1016/j.clpt.2005.11.01616580903)
Keller GA, et al. In vivo phenotyping methods: cytochrome p450 probes with emphasis on the cocktail approach. Curr Pharm Des. 2017;23(14):2035–49. (PMID: 10.2174/138161282366617020710072428176665)
de Jonge H, et al. Impact of CYP3A5 genotype on tacrolimus versus midazolam clearance in renal transplant recipients: new insights in CYP3A5-mediated drug metabolism. Pharmacogenomics. 2013;14(12):1467–80. (PMID: 10.2217/pgs.13.13324024898)
Yu KS, et al. Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states. Clin Pharmacol Ther. 2004;76(2):104–12. (PMID: 10.1016/j.clpt.2004.03.00915289787)
Backman JT, Olkkola KT, Neuvonen PJ. Rifampin drastically reduces plasma concentrations and effects of oral midazolam. Clin Pharmacol Ther. 1996;59(1):7–13. (PMID: 10.1016/S0009-9236(96)90018-18549036)
Krishna G, et al. Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: a phase I, randomized, open-label, crossover study in healthy volunteers. Clin Ther. 2009;31(2):286–98. (PMID: 10.1016/j.clinthera.2009.02.02219302901)
Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther. 1994;55(5):481–5. (PMID: 10.1038/clpt.1994.608181191)
Kashuba AD, et al. Quantification of 3-month intraindividual variability and the influence of sex and menstrual cycle phase on CYP3A activity as measured by phenotyping with intravenous midazolam. Clin Pharmacol Ther. 1998;64(3):269–77. (PMID: 10.1016/S0009-9236(98)90175-89757150)
Kharasch ED, et al. Intraindividual variability in male hepatic CYP3A4 activity assessed by alfentanil and midazolam clearance. J Clin Pharmacol. 1999;39(7):664–9. (PMID: 10.1177/0091270992200829010392320)
Kvitne KE, et al. Short- and long-term effects of body weight loss following calorie restriction and gastric bypass on CYP3A-activity—a non-randomized three-armed controlled trial. Clin Transl Sci. 2022;15(1):221–33. (PMID: 10.1111/cts.1314234435745)
Rogers JF, et al. An evaluation of the suitability of intravenous midazolam as an in vivo marker for hepatic cytochrome P4503A activity. Clin Pharmacol Ther. 2003;73(3):153–8. (PMID: 10.1067/mcp.2003.2312621380)
Kirwan C, MacPhee I, Philips B. Using drug probes to monitor hepatic drug metabolism in critically ill patients: midazolam, a flawed but useful tool for clinical investigation of CYP3A activity? Expert Opin Drug Metab Toxicol. 2010;6(6):761–71. (PMID: 10.1517/17425255.2010.48292920402562)
Klotz U, Ziegler G. Physiologic and temporal variation in hepatic elimination of midazolam. Clin Pharmacol Ther. 1982;32(1):107–12. (PMID: 10.1038/clpt.1982.1337083724)
Egeland EJ, et al. Chronic inhibition of CYP3A is temporarily reduced by each hemodialysis session in patients with end-stage renal disease. Clin Pharmacol Ther. 2020;108(4):866–73. (PMID: 10.1002/cpt.187532356565)
R Foundation for Statistical Computing. R: a language and environment for statistical computing 2018, Vienna, Austria.
Neely M, et al. Accurate Detection of outliers and subpopulations with Pmetrics a nonparametric and parametric pharmacometric modeling and simulation packagefor R. Thera Drug Monit. 2012;34:467–76. (PMID: 10.1097/FTD.0b013e31825c4ba6)
Abuhelwa AY, et al. Food, gastrointestinal pH, and models of oral drug absorption. Eur J Pharm Biopharm. 2017;112:234–48. (PMID: 10.1016/j.ejpb.2016.11.03427914234)
Jamei M, et al. Population-based mechanistic prediction of oral drug absorption. AAPS J. 2009;11(2):225–37. (PMID: 10.1208/s12248-009-9099-y193818402691459)
Matthaei J, et al. Inherited and acquired determinants of hepatic CYP3A activity in humans. Front Genet. 2020;11:944. (PMID: 10.3389/fgene.2020.00944329738807472781)
Kharasch ED, et al. Menstrual cycle variability in midazolam pharmacokinetics. J Clin Pharmacol. 1999;39(3):275–80. (PMID: 10.1177/00912700990390031110073327)
Zou P. Does food affect the pharmacokinetics of non-orally delivered drugs? A review of currently available evidence. AAPS J. 2022;24(3):59. (PMID: 10.1208/s12248-022-00714-035488003)
van Rongen A, et al. Population pharmacokinetic model characterizing 24-hour variation in the pharmacokinetics of oral and intravenous midazolam in healthy volunteers. CPT Pharmacomet Syst Pharmacol. 2015;4(8):454–64. (PMID: 10.1002/psp4.12007)
Tomalik-Scharte D, et al. Population pharmacokinetic analysis of circadian rhythms in hepatic CYP3A activity using midazolam. J Clin Pharmacol. 2014;54(10):1162–9. (PMID: 10.1002/jcph.31824782075)
Processing Request
No Comments.