Sensitive and robust UPLC–MS/MS method to determine the gender-dependent pharmacokinetics in rats of emodin and its glucuronide

Abstract

The purpose of this research was to set up a sensitive and consistent UPLC-UV and UPLCMS/MS method to analyze emodin and its glucuronidated metabolite, and to determine how gender differences affect its pharmacokinetic behaviors. In addition, a breast cancer resistance protein inhibitor dipyridamole was used to test how significant the absolute oral biovailabilty of emodin or its glucuronide is increased. A sensitive and fast UPLC-MS/MS method was successfully applied to determine emodin and its metabolite in male and female SD rat plasma. The absolute oral bioavailability of emodin was extremely low whether in male rats (7.5%) and female rats (5%). Following a single intravenous injection of 4 mg/kg emodin, the emodin plasma concentration-time data fit for a good two-compartment model either in male or female SD rats. The t1/2α were 13.26±6.28min (male rats) and 13.52±7.28min (female rats). The t1/2β were 187.38±0.16min (male rats) and 118.50±83.09min (female rats). Emodin showed significant gender differences in i.v. PK profiles with higher AUC values in male (422.71 ± 163.40 mg*μg/ml) than female (282.52 ± 98.42 mg*μg/ml) SD rats (n=6). Emodin glucuronide was suggested a good fit for single compartmental model for the plasma emodin metabolite concentrations. The t1/2Ke were 167.40±50.91min(male rats) and 251.31±114.20min (female rats), the area under the curve (AUC0-∞, i.v.) were 2210.02 ± 950.09 mg*μg/ml and 1054.42 ± 290.31 mg*μg/ml (female rats)(n=6). There was no good fit for any PK compartmental model for the plasma concentration-time data for single dose oral administration of emodin (8mg/kg) and its metabolite. Analyzing the oral PK data using non-compartmental model, Cmax, Tmax and AUC0-∞, p.o. of emodin in male rats were: 0.31±0.094 were μg/ml, 18.00±6.71min and 65.76±34.77 mg*μg/ml respectively; whereas Cmax, Tmax and AUC0-∞, p.o. of emodin in female rats were: 0.039±0.011 μg/ml, 18.75±7.51min and 33.82±4.09 mg*μg/ml respectively. The parameters of emodin glucuronide were significant different with emodin, the Cmax, Tmax and AUC0-∞, p.o of emodin glucuronide in male rats were 6.69±1.06 μg/ml, 240min and 2261.89±655.87 mg*μg/ml respectively, in female rats, the Cmax, Tmax and AUC0-∞, p.o. were 1.81±0.58 μg/ml, 60min and 458.50±373.29 mg*μg/ml respectively. The absolute bioavailability of emodin glucuronide was 60% (male rats) and 15% (female rats). The absolute bioavailability of emodin was no significant changed (7.3%) in male rats by using dipyridamole, the bioavailability of metabolite of emodin was significant declined to 14.6%.

Traditional usages, botany, phytochemistry, pharmacology and toxicology of Polygonum multiflorum Thunb.: A review

“…The results showed that the bioavailability of gallic acid improved, and the absorption of TSG, polydatin and emodin from the processed product in rats was reduced compared with that obtained with the raw product . Some studies have found that stilbene glucoside and emodin were rapidly converted to glucuronide conjugates in rats after oral administration (Sun 2004;Liu et al, 2011). Further pharmacokinetic studies indicated that the AUC, C max and T 1/2 of emodin were increased after stilbene glucoside treatment, and the glucuronidation of the emodin levels was significantly inhibited.…”

Effect of piperine on the bioavailability and pharmacokinetics of emodin in rats

“…1). Emodin has been known to have numerous pharmacological effects, including laxative, anti-allergic, anti-inflammatory and anti-diabetic activities [1][2][3]. In traditional Chinese medicines, emodin has been generally used in obesity-related diseases because of its the laxative property [4].…”

Gender‐dependent pharmacokinetics of olaparib in rats determined by ultra‐high performance liquid chromatography/electrospray ionization tandem mass spectrometry

“…A number of drugs displayed gender‐dependent pharmacokinetics in rats, such as emodin (Liu et al, ), peiminine (Chen et al, ), ON123300 (Mudunuru et al, ) and diosbulbin B (Yang et al, ). Gender‐dependent pharmacokinetics can potentially impact the efficacy and safety of a medication.…”