Inhibitory effect of phloridzin and phloretin on glucuronidation of p-nitrophenol, acetaminophen and 1-naphthol: kinetic demonstration of the influence of glucuronidation metabolism on intestinal absorption in rats.
Intestinal glucuronidation and absorption of p-nitrophenol (p-NP), acetaminophen (APAP) and 1-naphthol (alpha-NA) in the presence of phloridzin (inhibitor of Na+/glucose cotransporter) and phloretin (aglycone of phloridzin) were studied. Glucuronides of p-NP, APAP and alpha-NA appeared on both the serosal and mucosal sides. The amounts of glucuronides on the serosal side were decreased in the presence of phloridzin and phloretin. p-NP, APAP and alpha-NA appeared on the serosal side as well, and the amounts of p-NP, APAP and alpha-NA on the serosal side were increased by the presence of phloridzin and phloretin. Furthermore, the intestinal glucuronidation and absorption of alpha-NA at various concentrations were studied in the presence and absence of phloretin. Metabolic clearance was decreased in the presence of phloretin, and the absorption clearance was increased. The higher concentrations of alpha-NA caused higher absorption clearance. The lower the metabolic clearance, the higher the absorption clearance. The relationship between glucuronidation metabolism and absorption in intestine was kinetically analyzed by the metabolic inhibition model. Complete inhibition of glucuronidation improved the intestinal absorption of alpha-NA, and the absorption clearance increased to 7.17 microliter/min/cm. The formation of phloretin and an unknown metabolite from phloridzin were observed. An unknown metabolite from phloretin was observed, and was suppressed by the presence of alpha-NA. This suggests that phloridzin was hydrolyzed to phloretin, which was metabolized to glucuronide, and thereby inhibited glucuronidation of p-NP, APAP and alpha-NA.
Mizuma
T
T
Department of Biopharmaceutics and Drug Rational Research Center, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-03, Japan. mizuma@ps.toyaku.ac.jp
Awazu
S
S
D000082:Acetaminophen / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005965:Glucuronates / Q000378:metabolism; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D009284:Naphthols / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism; D010693:Phloretin / Q000494:pharmacology*; D010695:Phlorhizin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D005965:Glucuronates; D009284:Naphthols; D009596:Nitrophenols; C029350:1-naphthol; D000082:Acetaminophen; D010695:Phlorhizin; D005966:Glucuronidase; D010693:Phloretin; C024836:4-nitrophenol