Contribution of a significant first-pass effect of dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate in the liver to its poor bioavailability in rats.
OBJECTIVE
The objective of this study was to investigate the mechanism responsible for the poor oral bioavailability of dimethyl-4',4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB), a hepatoprotective agent, in rats.


METHODS
DDB was intravenously administered to rats at doses of 0.2-1 mg/kg. To determine the hepatic first-pass effect in rats, DDB (1 mg/kg) was administered via the pyloric vein and the femoral vein. Direct measurement of intestinal permeability was attempted using Caco-2 cell monolayers and rat intestinal epithelium.


RESULTS
A moment analysis indicated that the volume of distribution and clearance remained unchanged with the magnitude of the dose, indicating that DDB exhibited linear pharmacokinetics. When the area under the curve for DDB after administration to the pyloric vein was compared with that after femoral vein administration, the ratio (F(H)) was found to be 0.294, indicating a significant first-pass effect for DDB. The permeability of DDB was high in the rat intestine (1.78 +/- 0.229 x 10(-5) cm/s) and in Caco-2 cell monolayers (6.8 +/- 0.70 x 10(-5) cm/s), suggesting that DDB, in soluble form, was readily permeable across the intestinal epithelium.


CONCLUSIONS
These observations indicated that despite the fact that DDB was readily permeable to the intestinal epithelium, a significant first-pass metabolism was associated with its pharmacokinetics in rats.
Yu
Kyung-Ha
KH
Department of Pharmaceutics, College of Pharmacy, Seoul National University, Seoul 121-742, South Korea.
Lee
Ye-Rie
YR
Ahn
Sung-Hoon
SH
Kim
Dae-Duk
DD
Shim
Chang-Koo
CK
Chung
Suk-Jae
SJ
D000818:Animals; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000097:blood / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D003998:Dicarboxylic Acids / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D001713:Biphenyl Compounds; D003998:Dicarboxylic Acids; C510843:dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate