First-pass metabolism

First-pass (presystemic) metabolism is the hepatic biotransformation of an orally administered drug as it passes from the gut via the portal circulation to the liver before reaching systemic circulation. For cannabis, oral THC is extensively metabolized in the liver by cytochrome P450 enzymes — primarily CYP2C9, with contributions from CYP3A4 — into 11-hydroxy-THC (11-OH-THC), an active metabolite equipotent or more potent than THC at CB1 and highly brain-penetrant, which is then further oxidized to 11-nor-9-carboxy-THC (THC-COOH), the terminal inactive metabolite (Huestis 2007; Stout & Cimino 2014 Drug Metab Rev). CBD is metabolized via CYP2C19 and CYP3A4. First-pass explains: (1) low oral bioavailability (4–12%); (2) why edibles feel stronger and longer-lasting than an equivalent inhaled dose despite lower parent-THC Cmax — because 11-OH-THC exposure is much higher orally; (3) CYP polymorphism-driven interindividual variability. Citations: Huestis MA. Chem Biodivers. 2007;4:1770-1804; Stout SM, Cimino NM. Drug Metab Rev. 2014;46:86-95; Grotenhermen F. Clin Pharmacokinet. 2003;42:327-360.