[Mechanism of oral absorption of panaxnotoginseng saponins].
OBJECTIVE
To study the mechanism of absorption after oral administration of panaxnotoginseng saponins (PNS).


METHODS
Caco-2 cells and rat models were applied to evaluate the degradation of both ginsenoside Rb1 (Rb1) and ginsenoside Rg1 (Rg1) in PNS in gastrointestinal lumen, and the transport mechanism of PNS across the intestinal mucosa, and the barrier function of stomach, intestine and liver involved in absorption process.


RESULTS
Rb1 and Rg1 proved to be readily eliminated in stomach, but stable in relatively neutral circumstance. Both Rb1 and Rg1 in PNS, especially for Rb1, degraded significantly in the contents of large intestine. However, both of them kept mainly intact in the contents of small intestine. Uptake of both Rb1 and Rg1 by Caco-2 cell monolayer was inhibited at low temperature, but not by cyclosporine A, and the change in the apical pH showed no pronounced effect. Uptake and transport were non-saturable and increased linearly with increasing of concentrations of Rb1 and Rg1 over the range of concentration tested, which indicated a passive transport. There was no significant difference of absorption characteristic between monomer (Rb1 and Rg1) and mixture (PNS). Uptake amount of Rg1 [(1.07 +/- 0.16) microg x mg(-1) (protein)] (C0 = 1 mg x mL(-1)) in Caco-2 cells was a little higher than that of Rb1 [(0.77 +/- 0.03) microg x mg(-1) (protein)] (C0 = 1 mg x mL(-1)). Meanwhile, apparent permeability coefficient of (5.9 +/- 1.0) x 10(-8) cm x s(-1) (C0 = 1 mg x mL(-1)) for Rb1 and (2.59 +/- 0.17) x 10(-7) cm x s(-1) (C0 = 1 mg x mL(-1)) for Rg1 from apical compartment to basolateral compartment predicted an incompletely absorption. Transports of both Rb1 and Rg1 were not influenced by cyclosporine A. The investigation on the pharmacokinetic behavior of Rb1 and Rg1 after different routes of administration to rats showed that the absolute bioavailability after peroral (po), intraduodenal (id), and portal venous (pv) administration is 0.71% , 2.75% and 65.77% respectively for Rb1, and 3.29%, 6.60% and 50.56% respectively for Rg1.


CONCLUSIONS
Transport across Caco-2 cell monolayer for PNS (include Rb1 and Rg1) is a simple passive diffusion process. No efflux transporters in Caco-2 cells and other components in PNS showed effects on it. The elimination in stomach, large intestine and liver contributed to the low bioavailability of PNS, but the low membrane permeability might be a more important factor dominating the extent of absorption.
Han
Min
M
School of Pharmacy, Fudan University, Shanghai 200032, China.
Han
Li-Mei
LM
Wang
Qing-Song
QS
Bai
Zhi-Hua
ZH
Fang
Xiao-Ling
XL
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D016572:Cyclosporine / Q000494:pharmacology; D036145:Ginsenosides / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D053723:Panax notoginseng / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012503:Saponins / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics*; D013696:Temperature
D036145:Ginsenosides; D012503:Saponins; C442759:ginsenoside Rb1; D016572:Cyclosporine; C035054:ginsenoside Rg1