Effect Of The Pharmacokinetics Of Albendazole, Albendazole Sulphoxide And Albendazole Sulphoxide Enantiomeric After Oral Administration Of Fluconazole, Erythromycin And Andthiamazole To Rats

Research purposes:Albendazole is one of benzimidazole anti-helminthic drugs, which has properties of broad spectrum, high efficiency, and low toxicity. Albendazole is used to cure disease induced by roundworm, pinworm, tapeworm, whipworm, hookworm, round fecal nematode, the effect work by metabolized to albendazole sulfoxide in vivo. Albendazole is transformed to albendazole sulfoxide by hepatic microsomal enzymes in vivo. Albendazole sulfoxide has a chiral center and two kinds of enantiomers:(-)-albendazole sulfoxide and (+)-albendazole sulfoxide, recently study showed that the kinds of enantiomers have different pharmacological activities. The study is based on albendazole and enantiomers special pharmacological activities; echinococcus needs long-term, high-dose medication and outbreaks easily on the midwest in China. In order to understand those drugs combining with albendazole and enantiomers, we study "Effect of the pharmacokinetics of albendazole, albendazole sulphoxide and albendazole sulphoxide enantiomeric after oral administration of fluconazole, erythromycin enteric-coated and thiamazole tablets to rats", intend to whether those drugs affect the competitive of metabolizing enzymes in vivo.It is different to take part in metabolize enzymes of albendazole(mainly on cytochrome P450 enzymes isoenzyme CYP3A4), and it produces the different amount of (-)-albendazole sulfoxide and (+)-albendazole sulfoxide, it exists obvious species differences. Combine Fluconazole (CYP3A4, CYP2C9 inhibitors), Erythromycin (CYP3A4 inhibitor and substrate) and methimazole (decease the activity of CYP2C、CYP2B6、CYP3A4 and CYP1A2) with albendazole, albendazole sulfoxide and enantiomer in rats. To further explain those drugs metabolize mechanism in vivo and combine with those drugs to affect accouts of producing enantiomer by changing pharmacokinetic regular. The same time, we study albendazole sulfoxide chiral drugs to supply theory by the chiral monomer pharmacokinetic and metabolic rules.Method:The albendazole sulfoxide hand monomer was splitted, preparation and analysis.We used the chiral polymer coating (amylose derivatives) silica as a chiral column packing, The mobile phase is N-hexane/isopropanol/diethylamine(80/20/0.1) at 35 ℃, at the rate of 1ml/min, under this condition, the albendazole sulfoxide hand monomer was splitted, preparation and analysis. We used specific rotation and Mass Spectrometric Analysis to ensure two kinds of absolute configuration of enantiomers.We chose SD rats divided into 14 groups after adaptive feeding, before experiment three days, every group was oral continually Erythromycin, fluconazole or methimazole, and the dose was based on human. The control group was not treated with drug. On the experiment day the rats were oral albendazole, albendazole sulfoxide or chiral enantiomer. And then according to blood collection time, we did orbital venous plexus blood and heparin plasma was separated by centrifugation; we measured the plasma concentration of albendazole sulfoxide or chiral enantiomer with HPLC, calculated on major pharmacokinetic parameters. And we had statistical analysis on concentration-time curve and pharmacokinetic parameters with DAS software.Result: Under the chromatographic conditions we splitted albendazole sulfoxide racemate, the result showed that the retention time of two enantiomers was 15.619 min and 24.383 min respectively. We used two enantiomers to do mass spectrum, the result showed the mass-to-charge ratio of the molecular ion peak of two compounds was 281, which was equal to albendazole sulfoxide. The fragment ion of peak albendazole sulfoxide off the propyl and demethoxydaunorubicin formylamino was 238 and 206 respectively, which corresponds to the fragmentation regularity of albendazole sulfoxide mass spectrometry. According to the determination of optical rotation, the retention time of compound was 15.619min and the optical rotation value was+108°, which was albendazole sulfoxide oflx; the retention time of compound was 15.619min and the optical rotation value was+108°, which was (+)-ABZSO; the retention time of compound was24.383 min and the optical rotation value was-105°, which was (-)-ABZSO.The rats were oral albendazole, albendazole sulfoxide or chiral enantiomer, fluconazole, erythromycin and methimazole, we collected plasma, were analysis on blood drug concentration, drawed the plasma concentration-time curve, we had statistical analysis on concentration-time curve with DAS software, a main pharmacokinetic parameters are as follows:Table 2 Pharmacokinetic parameters of Albendazole, Albendazole sulfoxide, (+)-ABZSO And (-)-ABZSO of control groups The rats a single oral dose of 14 mg / kg albendazole,10 mg / kg of albendazole sulfoxide racemate and 5 mg / kg of (+)-ABZSO. The results showed: the AUC and relative bioavailability of albendazole sulfoxide racemate and (+)-ABZSO is higher then albendazole. the AUC of albendazole metabolism generate (-)-ABZSO and (+)-ABZSO was basically the same, the ratio was 1.06. After Oral albendazole sulfoxide, the AUC of (-)-ABZSO was higher then (+)-ABZSO, the difference is statistically significant. The AUC of a single oral of (-)-ABZSO and (+)-ABZSO was higher then albendazole sulfoxide metabolism. The above conclusions indicated that compared with albendazole, albendazole sulfoxide is used for treatment of related diseases has obvious advantages, the albendazole sulfoxide chiral monomer drug research and development have a significant scientific and clinical significance.Erythromycin can significantly improve the relative bioavailability of albendazole sulfoxide after oral ABZ, and the AUC of (+)-ABZSO increased by 1 times and of (-)-ABZSO was 0.5 times. But make the bioavailability after oral administration albendazole sulfoxide was significantly lower, (-)-ABZSO and (+)-ABZSO reducesd substantially the same level, AUC value of 3/4 of separate oral. Prompts in the course of treatment of hydatid disease and cysticercosis, pay attention to these drugs combine with erythromycin. Erythromycin inhibit CYP3A family enzymes, make the (-)-ABZSO generate relatively lower, but FMO major catalytic ABZ oxidation of (+)-ABZSO, its content of its mechanism of action is for further study.Fluconazole and methimazole make the AUC of albendazole sulfoxide values after oral albendazole was no significant impact. But make the bioavailability after oral administration of albendazole sulphoxide racemate substantial increased in rats body. The AUC ratio of ABZSO was 1.57 and 1.69, respectively, and AUC ratio of (+)-ABZSO was 1.72 and 1.87, the AUC ratio of (-)-ABZSO was 1.46 and 1.61. After single oral (-)-ABZSO and (+)-ABZSO, the drug concentration of (-)-ABZSO were no obvious change, the drug concentration of (+)-ABZSO was higherErythromycin, fluconazole and methimazole impact the pharmacokinetics dynamics of albendazole, albendazole sulfoxide. Compared with the other drugs, erythromycin are great (P <0.05), the other two drugs were no difference in statistically.