Abstract
We aimed to develop a berberine formulation to enhance the intestinal absorption and plasma concentrations of berberine through the inhibition of P-glycoprotein (P-gp)-mediated efflux and the intestinal metabolism of berberine in rats. We used pluronic P85 (P85) and tween 80, which have the potential to inhibit P-gp and cytochrome P450s (i.e., CYP1A2, 2C9, 2C19, 2D6, and 3A4). A berberine-loaded mixed micelle formulation with ratios of berberine: P85: tween 80 of 1:5:0.5 (w/w/w) was developed. This berberine mixed micelle formulation had a mean size of 12 nm and increased the cellular accumulation of digoxin via P-gp inhibition. It also inhibited berberine metabolism in rat intestinal microsomes, without significant cytotoxicity, up to a berberine concentration of 100 μM. Next, we compared the pharmacokinetics of berberine and its major metabolites in rat plasma following the oral administration of the berberine formulation (50 mg/kg) in rats with the oral administration of berberine alone (50 mg/kg). The plasma exposure of berberine was significantly greater in rats administered the berberine formulation compared to rats administered only berberine, which could be attributed to the increased berberine absorption by inhibiting the P-gp-mediated berberine efflux and intestinal berberine metabolism by berberine formulation. In conclusion, we successfully prepared berberine mixed micelle formulation using P85 and tween 80 that has inhibitory potential for P-gp and CYPs (CYP2C19, 2D6, and 3A4) and increased the berberine plasma exposure. Therefore, a mixed micelle formulation strategy with P85 and tween 80 for drugs with high intestinal first-pass effects could be applied to increase the oral absorption and plasma concentrations of the drugs.
Highlights
Berberine (Figure 1), an isoquinoline alkaloid isolated from Coptidis Rhizoma, has long been used as a folklore remedy in China for the treatment of bacteria-associated diarrhea and other gastrointestinal infections [1]
We investigated the inhibitory effect of P85 and tween 80 on five major cytochrome P450 (CYP) enzyme activities in human liver microsomes and on P-gp efflux function using LLC-PK1-P-gp cells
Representative inhibitors for the five CYPs and P-gp were used as a positive control (PC)
Summary
Berberine (Figure 1), an isoquinoline alkaloid isolated from Coptidis Rhizoma, has long been used as a folklore remedy in China for the treatment of bacteria-associated diarrhea and other gastrointestinal infections [1]. Berberine’s AUC value post intraduodenal administration was nearly 0.5% of its AUC value post intraportal vein administration These results suggest that first-pass elimination occurs predominantly in the rat intestine [8]. A total of 16 metabolites of berberine, 10 phase I metabolites, and 6 phase II metabolites were identified in the plasma, feces, bile, and other tissue samples of rats [9]. Among these metabolites, berberrubine, thalifendine, demethyleneberberine, and jatrorrhizine had relatively high plasma levels [10,11] and showed biological activities for antioxidative, hepatoprotective, and hypolipidemic effects [9]. Tuhseinbgaslaalbtroasaoplicinacl rteraasnesdpothrteoCf mbaexrabnedrinAeUwCasofmbuecrhbegrrineaeteinr trhatasnbtyhe1a.6p3ic-aalntdo b1.a5s4a-lfotrldan, srpesopret cotfivbeelyrb, ecroimnep, aarnedd wwaitshstighnosifiecoafnctloymdmecerrecaiasledtabbylettshe[2t5r]e,aatmltheonutgohf cthyecluonspdoerrliynienAg ,maercehparneissemnstaftoirvtehienihnicbrietoasreodf CPm-gaxpa[n1d2,A13U].CTohfebetrrebaetrmineenitnotfheknporewvnioPu-sgrpepinohrtisbwitoerrse, snuocthinavsecsyticglaotsepdo.rBinaeseAd,ovnertahpesaemriel,paonrtds,Cth2e19paunrptiobsoedoiefst,hiinscsrteuadseydwthase tboefrobremrinuelautepbtaekrbeeirninCeawcoit-h2 cthelelsp[1h3a,r1m4]a. cTehuitsicsaulggeexsctispitehnattsP-tghpatinmhiobdituolrattreeaPtm-gepntfsumncigtihotnaffaencdt thinetebsetribnearlinme eatbasboorlpistimon, parnodcetsos ainnvdesptihgaartme tahceokbiinoaetviacilparboilfiitlyesanodf bpehrabremrianceo.kiTnheteicuasleteoraftpiohnasromfabceerubteircianleeaxncdipiitesnmtsajtohramt metoabdoulliatetes Pin-grpa-tms,ediniatoerddeefflr utox ournidneterssttiannadl mtheteabroolliesmthcaotulpdhbaermusaecdeutoticinalcreexacseiptiheentbsiopavlaayilaibnilibtyioaanvdaiplalbasilmitya eexnphoasnucreemoefnbtearnbderpinhea.rmacokinetic modulation
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