Editing First pass effect (section)

== Drug design ==
In [[drug design]], drug candidates may have good [[druglikeness]] but fail on first-pass metabolism because it is biochemically [[Binding selectivity|selective]].{{Ambiguous|What is biochemically selective?|date=January 2024}} [[Physiologically based pharmacokinetic modelling|Physiologically based pharmacokinetic models]] (PBPK) are used to predict first-pass metabolism, although they require compound-specific adjustments due to variability in intestinal mucosal permeability and other factors.<ref name=":3">{{Cite journal |last1=Henriot |first1=Justine |last2=Dallmann |first2=André |last3=Dupuis |first3=François |last4=Perrier |first4=Jérémy |last5=Frechen |first5=Sebastian |date=2025 |title=PBPK modeling: What is the role of CYP3A4 expression in the gastrointestinal tract to accurately predict first-pass metabolism? |journal=CPT: Pharmacometrics & Systems Pharmacology |language=en |volume=14 |issue=1 |pages=130–141 |doi=10.1002/psp4.13249 |issn=2163-8306 |pmc=11706425 |pmid=39359052}}</ref><ref>{{Cite journal |last1=Heikkinen |first1=Aki T. |last2=Baneyx |first2=Guillaume |last3=Caruso |first3=Antonello |last4=Parrott |first4=Neil |date=2012-09-29 |title=Application of PBPK modeling to predict human intestinal metabolism of CYP3A substrates – An evaluation and case study using GastroPlus™ |url=https://linkinghub.elsevier.com/retrieve/pii/S0928098712002576 |journal=European Journal of Pharmaceutical Sciences |volume=47 |issue=2 |pages=375–386 |doi=10.1016/j.ejps.2012.06.013 |pmid=22759901 |issn=0928-0987|url-access=subscription }}</ref><ref name=":4">{{Cite journal |last1=Gertz |first1=Michael |last2=Harrison |first2=Anthony |last3=Houston |first3=J. Brian |last4=Galetin |first4=Aleksandra |date=2010 |title=Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data |url=https://linkinghub.elsevier.com/retrieve/pii/S0090955624024085 |journal=Drug Metabolism and Disposition |volume=38 |issue=7 |pages=1147–1158 |doi=10.1124/dmd.110.032649 |pmid=20368326 |issn=0090-9556|url-access=subscription }}</ref> Enzyme expression also varies between individuals, which may influence the efficiency of first-pass metabolism and thus the bioavailability of the drug.<ref name=":1" />

[[Cytochrome P450|Cytochromes P450]], especially [[CYP3A4]], play a crucial role in first-pass metabolism, affecting the bioavailability of drugs.<ref>{{Cite journal |last1=Jones |first1=Christopher R. |last2=Hatley |first2=Oliver J. D. |last3=Ungell |first3=Anna-Lena |last4=Hilgendorf |first4=Constanze |last5=Peters |first5=Sheila Annie |last6=Rostami-Hodjegan |first6=Amin |date=2016-05-01 |title=Gut Wall Metabolism. Application of Pre-Clinical Models for the Prediction of Human Drug Absorption and First-Pass Elimination |journal=The AAPS Journal |language=en |volume=18 |issue=3 |pages=589–604 |doi=10.1208/s12248-016-9889-y |issn=1550-7416 |pmc=5256607 |pmid=26964996}}</ref><ref name=":3" /><ref name=":4" />