The disposition of diammonium glycyrrhizinate and glycyrrhetinic acid in the isolated perfused rat intestine and liver.
The major component of liquorice root extract, glycyrrhizinate (GZ), has been formulated as an injection for the treatment of hepatitis. If given orally, GZ has poor bioavailability and is catalysed to glycyrrhetinic acid (GA) by intestinal bacteria. GA is subsequently responsible for significant side effects. This study was conducted to clarify the relationship between GZ and GA absorption and bioavailability. GZ and GA absorption were investigated using the in situ single pass isolated perfused intestine (IPI). Hepatic disposition was investigated using isolated perfused liver (IPL) and in vivo biliary excretion models. The apparent permeability and absorption rate constants in the IPI for GZ were 0.36 +/- 0.31 cm/min and 0.35 +/- 0.33 min (-1), while those for GA were 5.73 +/- 0.11 cm/min and 1.53 +/- 0.05 min (-1), respectively. The hepatic extraction ratios of unbound GZ and GA in the IPL were 0.22 +/- 0.01 and 0.44 +/- 0.15, respectively. Seven hours after intra-portal venous injection in vivo, the cumulative biliary excretion ratio for GZ was 96 %. There was negligible biliary excretion of unchanged GA during the same period. It was apparent in all models used that in the absence of intestinal bacteria GZ was not metabolised to GA, or vice versa. Hence, GZ can be absorbed unchanged from the intestine provided it has sufficient time and is protected from intestinal bacteria. This opens up the possibility that the use of pharmaceutical carrier systems or similar formulation approaches may allow effective oral administration of therapeutic levels of GZ without the side effects associated with GA.
Yang
Jin
J
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Zhou
Liang
L
Wang
Jiping
J
Wang
Guangji
G
Davey
Andrew K
AK
D000818:Animals; D006034:Glycyrrhetinic Acid / Q000378:metabolism / Q000493:pharmacokinetics*; D019695:Glycyrrhizic Acid / Q000378:metabolism / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D019695:Glycyrrhizic Acid; D006034:Glycyrrhetinic Acid