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Inhibition of baicalin on metabolism of phenacetin, a probe of CYP1A2, in human liver microsomes and in rats.

Gao N, Qi B, Liu FJ, Fang Y, Zhou J, Jia LJ, Qiao HL - PLoS ONE (2014)

Bottom Line: 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 C(60 min), t1/2, Vd and AUC (P<0.05).In conclusion, baicalin can inhibit the activity of CYP1A2 in HLMs and exhibit large inter-individual variation that has no relationship with gene polymorphism.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.

ABSTRACT
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(-1)protein 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 C(60 min), t1/2, Vd and AUC (P<0.05). There were significant correlations between percentage of control in C(60 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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Effect of baicalin at concentration ranged 0 from to 2000·L−1 on concentration of unbound phenacetin(%) in pooled rat plasma (n = 3).Total phenacetin concentration was 7·L−1. *indicates a significant (P<0.05) increase in concentration of unbound phenacetin (%) from blank value.
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pone-0089752-g006: Effect of baicalin at concentration ranged 0 from to 2000·L−1 on concentration of unbound phenacetin(%) in pooled rat plasma (n = 3).Total phenacetin concentration was 7·L−1. *indicates a significant (P<0.05) increase in concentration of unbound phenacetin (%) from blank value.

Mentions: In order to explain why Cmax of phenacetin decreased after treatment with baicalin, the effect of baicalin on rat plasma protein binding of phenacetin in vitro was studied. As shown in Figure 6, the unbound phenacetin (%) was 14.5%. It increased significantly when the concentration of baicalin was 250 mg·L−1. When the concentration of baicalin was 2000 mg·L−1, which was equivalent to the Cmax value in rat treated with baicalin (450 mg/kg), the concentration of unbound phenacetin (%) increased approximately 2-fold.


Inhibition of baicalin on metabolism of phenacetin, a probe of CYP1A2, in human liver microsomes and in rats.

Gao N, Qi B, Liu FJ, Fang Y, Zhou J, Jia LJ, Qiao HL - PLoS ONE (2014)

Effect of baicalin at concentration ranged 0 from to 2000·L−1 on concentration of unbound phenacetin(%) in pooled rat plasma (n = 3).Total phenacetin concentration was 7·L−1. *indicates a significant (P<0.05) increase in concentration of unbound phenacetin (%) from blank value.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3935934&req=5

pone-0089752-g006: Effect of baicalin at concentration ranged 0 from to 2000·L−1 on concentration of unbound phenacetin(%) in pooled rat plasma (n = 3).Total phenacetin concentration was 7·L−1. *indicates a significant (P<0.05) increase in concentration of unbound phenacetin (%) from blank value.
Mentions: In order to explain why Cmax of phenacetin decreased after treatment with baicalin, the effect of baicalin on rat plasma protein binding of phenacetin in vitro was studied. As shown in Figure 6, the unbound phenacetin (%) was 14.5%. It increased significantly when the concentration of baicalin was 250 mg·L−1. When the concentration of baicalin was 2000 mg·L−1, which was equivalent to the Cmax value in rat treated with baicalin (450 mg/kg), the concentration of unbound phenacetin (%) increased approximately 2-fold.

Bottom Line: 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 C(60 min), t1/2, Vd and AUC (P<0.05).In conclusion, baicalin can inhibit the activity of CYP1A2 in HLMs and exhibit large inter-individual variation that has no relationship with gene polymorphism.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Pharmacology, Zhengzhou University, Zhengzhou, People's Republic of China.

ABSTRACT
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(-1)protein 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 C(60 min), t1/2, Vd and AUC (P<0.05). There were significant correlations between percentage of control in C(60 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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