Pharmacokinetic changes of unbound theophylline are due to plasma protein binding displacement and CYP1A2 activity inhibition by baicalin in rats

Gao, Na; Fang, Yan; Qi, Bing; Liu, Jia; Han, Jin; Qiao, Huan

doi:10.1016/j.jep.2013.08.062

Cited by 10 publications

(8 citation statements)

References 27 publications

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“…It meant that the inhibition of baicalin in vivo seemed weak. This phenomenon might be related with displacement of phenacetin from plasma protein by baicalin [10], [11].…”

Section: Discussionmentioning

confidence: 97%

“…As a much stronger inhibitor of CYP1A2 in HLM, it should be paid more attention to the pharmacokinetic changes of phenacetin induced by baicalin in clinic. Our previous results showed that the AUC of theophylline had no significant change after treated by baicalin (450 mg/kg was administered at 0 h), a probe of CYP1A2 [11]. The results indicated that the inhibition of baicalin on the substrate of CYP1A2 was specific and the inhibition potency was stronger on phenacetin than that on theophylline.…”

Section: Discussionmentioning

confidence: 97%

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Inhibition of Baicalin on Metabolism of Phenacetin, a Probe of CYP1A2, in Human Liver Microsomes and in Rats

Gao

Liu

et al. 2014

PLoS ONE

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Baicalin has been used as mainly bioactive constituent of about 100 kinds of traditional Chinese medicines in Chinese pharmacopoeia. The effect of baicalin on cytochrome P450 should be paid more attention because baicalin was used widely. The aim of this study was to investigate whether baicalin could inhibit CYP1A2 in pooled human liver microsomes (HLMs) and in rats in vivo and the gene polymorphisms could affect inter-individual variation in IC50 in 28 human livers. Phenacetin was used as probe of CYP1A2. Kinetic parameter of CYP1A2 and IC50 of baicalin on CYP1A2 to each sample were measured and the common CYP1A2 polymorphisms (−3860G>A and −163C>A) were genotyped. The results showed that baicalin exhibited a mixed-type inhibition in pooled HLMs, with a Ki value of 25.4 µM. There was substantial variation in Km, Vmax, CLint of CYP1A2 and IC50 of baicalin on CYP1A2 (3∼10-fold). The range was from 26.6 to 114.8 µM for Km, from 333 to 1330 pmol·min−1·mg−1protein for Vmax and from 3.8 to 45.3 µL·min−1·mg−1 protein for CLint in HLMs (n = 28). The Mean (range) value of IC50 in 28 HLMs was 36.3 (18.9 to 56.1) µM. The genotypes of −3860G>A and −163C>A had no significant effect on the inhibition of baicalin on CYP1A2. The animal experiment results showed that baicalin (450 mg/kg, i.v.) significantly decreased the Cmax and CL of phenacetin, and increased C60 min, t1/2, Vd and AUC (P<0.05). There were significant correlations between percentage of control in C60 min, t1/2, CL, AUC of phenacetin and Cmax of baicalin in 11 rats (P<0.05). Protein binding experiments in vitro showed that baicalin (0–2000 mg/L) increased the unbound phenacetin from 14.5% to 28.3%. In conclusion, baicalin can inhibit the activity of CYP1A2 in HLMs and exhibit large inter-individual variation that has no relationship with gene polymorphism. Baicalin can change the pharmacokinetics of phenacetin in rats.

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“…It meant that the inhibition of baicalin in vivo seemed weak. This phenomenon might be related with displacement of phenacetin from plasma protein by baicalin [10], [11].…”

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Inhibition of Baicalin on Metabolism of Phenacetin, a Probe of CYP1A2, in Human Liver Microsomes and in Rats

Gao

Liu

et al. 2014

PLoS ONE

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“…For the evaluation of effects of intestinal microbiota, the administration route of either baicalin or baicalein and test drugs in clinical settings should be carefully considered. In this regard, some studies which evaluated the drug interaction of either baicalin or baicalein with certain drugs have been conducted following the intravenous co-injection of these compounds in vivo [38,39,42,43]. When considering the pre-systemic metabolism of baicalin and baicalein in the intestine, drug interaction study with either baicalin or baicalein should also be conducted after oral administration in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…Those changes in C max , t 1/2 , CL and AUC of theophylline by baicalin may be also attributed to two mechanisms, i.e. , plasma protein binding displacement and inhibition of CYP1A2 activity [39].…”

Section: Baicalin and Baicalein Induced In Vivo Drug Interactionmentioning

confidence: 99%

Role of Intestinal Microbiota in Baicalin-Induced Drug Interaction and Its Pharmacokinetics

et al. 2016

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Since many glycoside compounds in natural products are hydrolyzed by intestinal microbiota when administered orally, it is of interest to know whether their pharmacological effects are derived from the glycoside itself or from the aglycone form in vivo. An interesting example is baicalin versus baicalein, the aglycone of baicalin, which is contained in some herbs from Labiatae including Scutellaria baicalensis Georgi and Scutellaria lateriflora Linne. The herbs have been extensively used for treatment of inflammatory diseases in Asia. Although there have been numerous reports regarding the pharmacological effects of baicalin and baicalein in vivo and in vitro, some reports indicated that the glycoside form would hardly be absorbed in the intestine and that it should be hydrolyzed to baicalein in advance for absorption. Therefore, the role of metabolism by intestinal microbiota should also be considered in the metabolism of baicalin. In addition, baicalin contains a glucuronide moiety in its structure, by which baicalin and baicalein show complex pharmacokinetic behaviors, due to the interconversion between them by phase II enzymes in the body. Recently, concerns about drug interaction with baicalin and/or baicalein have been raised, because of the co-administration of Scutellaria species with certain drugs. Herein, we reviewed the role of intestinal microbiota in pharmacokinetic characteristics of baicalin and baicalein, with regards to their pharmacological and toxicological effects.

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“…The reasons lending to this phenomenon are complex while one of which may be the effect of protein binding rate. It is well known that when two or more drugs are administrated in combination, the competition for the protein among them may occur [35,36]. While, the change of protein binding can alter the unbound drug concentrations which is responsible for drug efficacy and potential drug toxicity.…”

mentioning

confidence: 99%

Pretreatment of plasma samples by a novel hollow fiber centrifugal ultrafiltration technique for the determination of plasma protein binding of three coumarins using acetone as protein binding releasing agent

Shi

Jiang

et al. 2015

Journal of Chromatography B

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Pharmacokinetic changes of unbound theophylline are due to plasma protein binding displacement and CYP1A2 activity inhibition by baicalin in rats

Cited by 10 publications

References 27 publications

Inhibition of Baicalin on Metabolism of Phenacetin, a Probe of CYP1A2, in Human Liver Microsomes and in Rats

Inhibition of Baicalin on Metabolism of Phenacetin, a Probe of CYP1A2, in Human Liver Microsomes and in Rats

Role of Intestinal Microbiota in Baicalin-Induced Drug Interaction and Its Pharmacokinetics

Pretreatment of plasma samples by a novel hollow fiber centrifugal ultrafiltration technique for the determination of plasma protein binding of three coumarins using acetone as protein binding releasing agent

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