Table 1.

Examples of route-dependent intestinal metabolism.

Compound	System	Enzyme/Metabolite	Examples	References
Enalapril	Perfused rat intestine–liver preparation	Esterase/enalaprilat	Enalaprilat formed from enalapril after po administration but not systemic administration	[62]
Acetaminophen	Perfused rat small intestine preparation	Ugt1a6/acetaminophen glucuronide	Metabolite observed after intraduodenal but not systemic dosing	[63]
(-)-6-aminocarbovir (6AC)	Perfused rat small intestine preparation	Adenosine deaminase activates (-)-carbovir to 6AC	6AC was highly extracted by intestine after luminal dosing (0.54) compared to reservoir dosing (0.08)	[64]
Morphine	Perfused rat small intestine preparation	Ugt2b1/ morphine 3-glucuronide (M3G)	M3G appeared after intraduodenal but not systemic dosing	[61]
L-754,394, (furanopyridine derivative)	Rats and dogs in vivo and rat liver perfusion	Cyp3a/ epoxide intermediate	Inhibition of L-754,394 and its metabolites by Cyp3a is much greater for po than iv administration of drug	[65]
Cyclosporine	Human in vivo	CYP3A4/AM1 and AM9	Metabolites: AM1 and AM9 are lower after iv compared to po	[66]
Verapamil	Human in vivo	CYP3A4 and 3A5/ norverapamil	Metabolite, norverapamil formation after po > iv	[67]
Hydralazine	Human in vivo	Acetyltransferase/ 3-methyl-striazolo-3,4, α-phthalazine (MTP)	More MTP formation observed after oral dosing than iv dosing	[68]
Cyclobenzaprine	Human in vivo	UGT/ cyclobenzaprine glucuronide (CBG)	Formation of CBG was greater for the oral than for parenteral case	[69]
Midazolam (MDZ)	Human in vivo	CYP3A4/ 1’-OH and 4-OH MDZ	EI after intraduodenal administration >> EI for iv administration	[59,70]
Methyldopa	Human in vivo	SULT/ methyldopa sulfate (MS)	Greater formation of MS after po than iv dosing of M	[71]
Quinidine	Human in vivo	CYP3A/ 3-hydroxyquinidine	More 3-hydroxyquinidine formed via oral compared to iv route	[72]