First-pass metabolism substantially reduces oral bioavailability of some drugs. Which cytochrome P450 enzyme is predominantly responsible for first-pass metabolism in the gut wall (not just liver) of drugs like cyclosporine and midazolam?
- A CYP2C9 in intestinal enterocytes
- B CYP1A2 in the duodenum
- C CYP3A4/3A5 expressed in enterocytes of the small intestinal wall — accounts for 50–80% of intestinal first-pass for CYP3A4 substrates before hepatic first-pass ✓
- D MAO-A in the intestinal mucosa
Explanation
CYP3A4 is abundantly expressed in the enterocytes lining the small intestine (particularly the jejunum), where it forms a significant metabolic barrier for orally administered drugs. For CYP3A4 substrates like cyclosporine, midazolam, and felodipine, gut-wall CYP3A4 can account for 50–80% of total first-pass extraction. Grapefruit juice inhibits intestinal CYP3A4 (and P-gp) specifically, dramatically increasing bioavailability of affected drugs without much effect on hepatic CYP3A4 (because inhibitory furanocoumarins undergo first-pass themselves). This is the basis for drug-grapefruit juice interactions.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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