First-Pass Metabolism: Drug Lost Before It Reaches the Blood (Absorption 2.3)

Why does so little of some oral drugs reach the blood? Lesson 2.3 of our absorption module covers first-pass metabolism in the gut wall and the liver, the fractions Fg and Fh, and the routes that avoid the first pass. Two studies of midazolam show how much drug each organ removes. Transcript, equations and practice questions: https://freefraction.com/lessons/2-3-... 0:00 First-pass metabolism 1:41 The gut wall 2:21 The liver 2:53 Extraction and variability 4:08 Routes that avoid the first pass 4:35 Midazolam 6:04 Buccal midazolam 6:39 Summary Sources Trevaskis NL, Charman WN, Porter CJ. Lipid-based delivery systems and intestinal lymphatic drug transport: a mechanistic update. Adv Drug Deliv Rev. 2008. PMID 18155316 Shen DD, Kunze KL, Thummel KE. Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. Adv Drug Deliv Rev. 1997. PMID 10837554 Varma MV, Obach RS, Rotter C, et al. Physicochemical space for optimum oral bioavailability: contribution of human intestinal absorption and first-pass elimination. J Med Chem. 2010. PMID 20070106 Paine MF, Hart HL, Ludington SS, et al. The human intestinal cytochrome P450 "pie". Drug Metab Dispos. 2006. PMID 16467132 Zhang H, Zhang J, Streisand JB. Oral mucosal drug delivery: clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet. 2002. PMID 12126458 Thummel KE, O'Shea D, Paine MF, et al. Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A-mediated metabolism. Clin Pharmacol Ther. 1996. PMID 8646820 Kvitne KE, Drevland OM, Haugli N, et al. Intraindividual variability in absolute bioavailability and clearance of midazolam in healthy individuals. Clin Pharmacokinet. 2023. PMID 37162619 Schwagmeier R, Alincic S, Striebel HW. Midazolam pharmacokinetics following intravenous and buccal administration. Br J Clin Pharmacol. 1998. PMID 9764959 Darwish M, Kirby M, Robertson P, et al. Absolute and relative bioavailability of fentanyl buccal tablet and oral transmucosal fentanyl citrate. J Clin Pharmacol. 2007. PMID 17322146 Illustrations adapted from Servier Medical Art (smart.servier.com), CC BY 4.0. Structures drawn with RDKit.