Extensive intestinal first-pass elimination and predominant hepatic distribution of berberine explain its low plasma levels in rats

Absolute oral bioavailability of berberine is below 1% in rats and below a few percent in humans.

“The absolute oral bioavailability of berberine is very low, estimated to be below 1% in rats and below a few percent in humans [48,49,50]”

Low bioavailability of berberine is a consequence of P-glycoprotein-mediated efflux and extensive intestinal and hepatic first-pass metabolism.

“a consequence of its physicochemical properties and of the limited absorption consistently documented in the literature [51,52,53] of P-glycoprotein-mediated efflux and of extensive intestinal and hepatic first-pass metabolism [48,54,55].”

Berberine reaches high intraluminal and enterocytic concentrations, at the level where absorption and first-pass metabolism of orally administered drugs occur.

“berberine reaches high intraluminal and enterocytic concentrations, exactly at the level where absorption and first-pass metabolism of orally administered drugs occur [48,54].”

Quantifying the local exposure that matters for interactions cannot be inferred from plasma concentrations but requires dedicated methods.

“Quantifying the local exposure that truly matters for interactions cannot be inferred from plasma concentrations but requires dedicated methods [48,62].”

Low systemic exposure does not protect against interactions; rather, it shifts their site toward the absorption and elimination interfaces, where local concentrations are high.

“In summary, low systemic exposure does not protect against interactions; rather, it shifts their site toward the absorption and elimination interfaces, where local concentrations are high (Figure 1) [37,43,48].”

The quality and transferability of each piece of evidence were appraised qualitatively, bearing in mind that, in preclinical models, berberine concentrations may exceed human systemic exposure.

“The quality and transferability of each piece of evidence were appraised qualitatively, bearing in mind that, in preclinical models, berberine concentrations may exceed human systemic exposure [48,68].”

An important part of the mechanistic evidence comes from in vitro and preclinical studies, in which berberine concentrations may exceed human systemic exposure; the clinical transferability of these data must therefore be interpreted with caution.

“An important part of the mechanistic evidence comes from in vitro and preclinical studies, in which berberine concentrations may exceed human systemic exposure [48,68]; the clinical transferability of these data must therefore be interpreted with caution [64,68].”

The translational gap is constitutive of the field: in vitro concentrations that produce inhibition exceed human plasma concentrations by two to four orders of magnitude; local concentrations that would bridge the gap have been calculated but not measured in humans; PBPK models that would connect the two have not been validated against clinical data for berberine; and the human endpoints available

“The in vitro concentrations that produce inhibition exceed human plasma concentrations by two to four orders of magnitude, as Section 2.1 sets out; the local concentrations that would bridge the gap have been calculated but not measured in humans; the PBPK models that would connect the two have not been validated against clinical data for berberine; and the human endpoints available are surrogates”