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

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−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.

In vitro inhibitory effects of herbal supplements on tamoxifen and irinotecan metabolism

“…This could be due in part to the formation of this active metabolite having multiple pathways and involving multiple enzymes, thereby allowing for numerous opportunities for inhibition in the measured reaction velocities. Gao et al have previously reported that baicalin inhibits human CYP1A2 via mixed type inhibition using phenacetin as a probe [13]. Because CYP1A2 contributes to the formation of DES, which is the one precursor metabolites to ENDO, inhibiting this enzyme would reduce the amount of ENDO formed which is consistent with our data.…”

Significant change of cytochrome P450s activities in patients with hepatocellular carcinoma

“…We defined ‘smokers’ as those who smoke 11 cigarettes or more smoking per day, ‘non-smokers’ as individuals who had never smoked or smoke less than 11 cigarettes per day. The standard referred the previous method [28]. …”

Effects of Baicalin on Oral Pharmacokinetics of Caffeine in Rats

“…Both compounds might not affect other CYPs, including CYP 2E1 and 3A, at the concentrations tested (∼100 μM). These results were consistent with previous reports ( Gao et al ., 2013 ; Gao et al ., 2014 ). Gao et al .…”

“…For an example, baicalein significantly increased the CYP3A4 activity in vitro , whereas the pharmacokinetics of certain drugs metabolized by CYP3A4 were inhibitedly altered in the presence of baicalein ( Cho et al ., 2011 ; Li et al ., 2011 ). The effects of baicalin on drug metabolism were also evaluated through in vivo studies ( Gao et al ., 2013 ; Gao et al ., 2014 ). Considering these results, the effects of baicalin and baicalein on CYP isozymes and pharmacokinetics of certain drugs needed to be re-evaluated.…”