Baicalin is a substrate of OATP2B1 and OATP1B3

Kalapos-Kovács, Bernadett; Juhász, Viktória; Temesszentandrási-Ambrus, Csilla; Magda, Balázs; Szabó, Pál; Antal, István; Klebovich, Imre; Krajcsi, Péter

doi:10.1002/ptr.6095

Cited by 7 publications

(3 citation statements)

References 9 publications

(15 reference statements)

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“…A previous study has identified baicalin as a substrate for both OATP1B3 and OATP2B1 [36]. In our current study, the accumulation of baicalin in HEK-OAT1, HEK-OAT3, and HEK-OATP1B3 cells was about 4.0-, 3.9-, and 2.8-fold higher than that in HEK-EV cells, respectively (▶ Fig.…”

Section: Resultssupporting

confidence: 61%

Potential Involvement of Organic Anion Transporters in Drug Interactions with Shuganning Injection, a Traditional Chinese Patent Medicine

Xing

Gui

et al. 2023

Planta Med

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Traditional Chinese medicine injections have been widely used in China for the treatment of various diseases. Transporter-mediated drug-drug interactions are a major contributor to adverse drug reactions. However, the research on transporter-mediated Traditional Chinese medicine injection-drug interactions is limited. Shuganning injection is a widely used Traditional Chinese medicine injection for treating various liver diseases. In this study, we investigated the inhibitory effect of Shuganning injection and its four main ingredients (baicalin, geniposide, chlorogenic acid, and oroxylin A) on 9 drug transporters. Shuganning injection strongly inhibited organic anion transporter 1 and organic anion transporter 3 with IC50 values < 0.1% (v/v), and moderately inhibited organic anion transporter 2, organic anion transporting-polypeptide 1B1, and organic anion transporting-polypeptide 1B3 with IC50 values < 1.0%. Baicalin, the most abundant bioactive ingredient in the Shuganning injection, was identified as both an inhibitor and substrate of organic anion transporter 1, organic anion transporter 3, and organic anion transporting-polypeptide 1B3. Oroxylin A had the potential to act as both an inhibitor and substrate of organic anion transporting-polypeptide 1B1 and organic anion transporting-polypeptide 1B3. In contrast, geniposide and chlorogenic acid had no significant inhibitory effect on drug transporters. Notably, Shuganning injection markedly altered the pharmacokinetics of furosemide and atorvastatin in rats. Using Shuganning injection as an example, our findings support the implementation of transporter-mediated Traditional Chinese medicine injection-drug interactions in the development of Traditional Chinese medicine injection standards.

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Section: Resultssupporting

confidence: 61%

Potential Involvement of Organic Anion Transporters in Drug Interactions with Shuganning Injection, a Traditional Chinese Patent Medicine

Xing

Gui

et al. 2023

Planta Med

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“…After oral administration, BG, due to low lipophilicity, may either be directly absorbed by the action of uptake transporters, or undergo hydrolysis by intestinal glucuronidase or intestinal microflora to release its aglycone B (Akao et al., 2010; Kang et al., 2014; Noh et al., 2016; Kalapos-Kovács et al., 2018). B is probably better absorbed and then efficiently conjugated to BG in the gut wall and the liver and thus restored to its original form BG (baicalein 7-O-glucuronide) as well as to baicalein 6-O-glucuronide (Liu et al., 2009; Zhang et al., 2011).…”

Section: Discussionmentioning

confidence: 99%

A Single Dose of Baicalin Has No Clinically Significant Effect on the Pharmacokinetics of Cyclosporine A in Healthy Chinese Volunteers

Liu

Wei

et al. 2019

Front. Pharmacol.

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Despite its narrow therapeutic window and large interindividual variability, cyclosporine A (CsA) is the first-line therapy following organ transplantation. Metabolized mainly by CYP3A and being a substrate of P-glycoprotein (P-gp), CsA is susceptible to drug–drug interactions. Baicalin (BG) is a drug used for adjuvant therapy of hepatitis in traditional Chinese medicine. Since its aglycone baicalein (B) inhibits CYP3A and P-gP, co-administration might affect CsA pharmacokinetics. This study investigated the effect of BG on CsA pharmacokinetics. In a two-period study, 16 healthy volunteers received a single 200 mg oral CsA dose alone (reference period) or in combination with 500 mg BG (test period). Pharmacokinetic evaluation of CsA was carried out using non-compartmental analysis (NCA) and population pharmacokinetics (popPK). Treatments were compared using the standard bioequivalence method. Based on NCA, 90% CIs of AUC and C max test-to-reference ratios were within bioequivalence boundaries. In the popPK analysis, a two-compartment model (clearance/F 62.8 L/h, central and peripheral volume of distribution/F 254 L and 388 L) with transit compartments for absorption appropriately described CsA concentrations. No clinically relevant effect of 500 mg BG co-administration on CsA pharmacokinetics was identified and both treatments were well tolerated.

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“…Along with the growth in the clinical applicability of BG, there is increasing concern over the drug interactions with BG during coadministration with other agents ( Li-Weber, 2009 ; Boniface and Elizabeth, 2019 ). Notably, for treatment of patients with complex disease states, BG exhibited synergistic interactions with many combination drugs by regulating drug-metabolizing enzymes and/or drug transporters to decrease/enhance their efficacy and reduce/increase toxicity in the complex therapeutic regimens ( Kalapos-Kovacs et al, 2015 ; Kalapos-Kovacs et al, 2018 ; Zhou et al, 2021 ). We elucidated that BG varies the pharmacokinetics of phenacetin, theophylline, midazolam, dextromethorphan, nifedipine, and chlorzoxazone in rats by regulating the metabolism of CYP1A2, CYP2E1, CYP3A, and CYP2D in previous studies ( Gao et al, 2013 ; Tian et al, 2013a ; Tian et al, 2013b ; Cheng et al, 2014 ; Gao et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption

et al. 2021

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Background: Sorafenib (SOR) is an oral, potent, selective, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used as the first-line therapy for advanced hepatocellular carcinoma (HCC). Baicalin (BG) is used as adjuvant therapy for hepatitis, which accounts for the leading cause of the development of HCC, and is commonly coadministered with SOR in clinic. The purpose of the current study was to characterize the pharmacokinetic changes of SOR and the potential mechanism when SOR is administered concomitantly with BG in rats for single and multiple doses.Methods: Parallel randomized pharmacokinetic studies were performed in rats which received SOR (50 mg/kg, i.g.) alone or coadministered with BG (160 mg/kg, i.g.) for single and multiple doses (7 days). Plasma SOR levels were quantified by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). Rat liver microsomes (RLMs) which isolated from their livers were analyzed for CYP3A and SOR metabolism activities. The inhibitory effect of BG on the metabolism of SOR was also assessed in pooled human liver microsomes (HLMs). The effects of BG on the intestine absorption behaviors of SOR were assessed in the in situ single-pass rat intestinal perfusion model.Results: Coadministration with BG (160 mg/kg, i.g.) for single or multiple doses significantly increased the Cmax, AUC0–t, and AUC0–∞ of orally administered SOR by 1.68-, 1.73-, 1.70-fold and 2.02-, 1.65-, 1.66- fold in male rats and by 1.85-, 1.68-, 1.68-fold and 1.57-, 1.25-, 1.24- fold in female rats, respectively (p < 0.01 or p < 0.05). In vitro incubation assays demonstrated that there were no significant differences of Km, Vmax, and CLint of 1-OH MDZ and SOR N-oxide in RLMs between control and multiple doses of BG-treated groups. BG has no obvious inhibitory effects on the metabolism of SOR in HLMs. In comparison with SOR alone, combining with BG significantly increased the permeability coefficient (Peff) and absorption rate constant (Ka) of the SOR in situ single-pass rat intestinal perfusion model.Conclusion: Notably enhanced oral bioavailability of SOR by combination with BG in rats may mainly account for BG-induced SOR absorption. A greater understanding of potential DDIs between BG and SOR in rats makes major contributions to clinical rational multidrug therapy in HCC patients. Clinical trials in humans and HCC patients need to be further confirmed in the subsequent study.

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Baicalin is a substrate of OATP2B1 and OATP1B3

Cited by 7 publications

References 9 publications

Potential Involvement of Organic Anion Transporters in Drug Interactions with Shuganning Injection, a Traditional Chinese Patent Medicine

Potential Involvement of Organic Anion Transporters in Drug Interactions with Shuganning Injection, a Traditional Chinese Patent Medicine

A Single Dose of Baicalin Has No Clinically Significant Effect on the Pharmacokinetics of Cyclosporine A in Healthy Chinese Volunteers

Baicalin Enhanced Oral Bioavailability of Sorafenib in Rats by Inducing Intestine Absorption

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