Oral Absorption of Ginsenoside Rb₁ using in vitro and in vivo Models

Abstract

This research attempts to clarify the cause for poor oral absorption of ginsenoside Rb₁ (Rb₁), one main ingredient of the well known Panax notoginseng saponins (PNS) for curing hemorrhage. Caco-2 cell monolayers were used as an in vitro model to reveal the transport mechanism of Rb₁ across the intestinal mucosa. Moreover, the serum concentration-time profiles of Rb₁ after tail venous (IV), portal venous (PV), intraduodenal (ID) and peroral (PO) administration to rats were compared to evaluate the first-pass effects of stomach, intestine and liver. In vitro experiments showed that uptake by Caco-2 cell monolayers was temperature dependent, but was not influenced by cyclosporine A and ketoconazole. The change in the apical pH showed no obvious effects on the uptake of Rb₁. The uptake and transport were non-saturable, and flux from the apical compartment to the basolateral compartment (A - B) increased linearly with increasing concentration, which indicated a passive transport. Meanwhile, an apparent permeability coefficient of (5.90 ± 1.02) × 10^-8 cm/s (C₀ = 1 mg/mL) predicted an incomplete absorption. The investigation on the pharmacokinetic behavior of Rb₁ after different routes of administration to rats showed a significant difference between PO (F_PO was 0.64 %), ID (F_ID was 2.46 %) and PV (F_PV was 59.49 %) administration, and the first-pass effect of the intestine is more significant than that of the stomach and liver in the absorption process. In summary, elimination in the stomach, large intestine and liver contributed to the poor absorption of Rb₁, but the low membrane permeability might be a more important factor dominating the extent of absorption.

Abbreviations

Rb₁:ginsenoside Rb₁

PNS:Panax notoginseng

A:apical

B:basolateral

HEPES:N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid

MES:2-N-morpholineethanesulfonic acid

HBSS:Hanks balanced salt solution

CsA:cyclosporine A

KCZ:ketoconazole

P_app:apparent permeability coefficient

PO:peroral (administration)

ID:intraduodenal (administration)

PV:portal venous (administration)

IV:tail venous (administration)

F_PO:absolute bioavailability after peroral administration

F_ID:absolute bioavailability after intraduodenal administration

F_PV:absolute bioavailability after portal venous administration

F_IV:absolute bioavailability after tail venous administration

Ginsenoside Rb₁ - Panax notoginseng - Caco-2 - bioavailability

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