Comparative Studies Of Effects Of Two Novel Marine Drug 911,971 On CYP 450 Subtype Enzymes And Their Sexual Differences

In human liver, CYP1A2, CYP3A4 and CYP2E1 are the most important subtype enzymes of CYP450, which play a critical role in drug metabolism. Many factors can cause the differences of drug effect and their metabolism by affecting CYP 450 activity. It is a known fact that the induction or inhibition on CYP 450 isomers by some drugs is highly structure dependent. And the variations in molecular skeletons characterized by differences in spatial configuration, steric hindrance and even their physical and/or chemical properties, including hydropathicity or hydrophobicity, etc., also play important roles in modulating enzyme activities.A sulfated polymannuroguluronate, SPMG-911 (abbreviated as 911), and an acidic oligosaccharide sugar chain compound, AOSC-971 (abbreviated as 971), are both Class I drugs invented by the Marine Drug and Food Institute of Ocean University of China. Although they are both sugar-based drug, there are still some differences in molecular skeletons, satiric hindrance and even their physical and/or chemical properties, like molecular weight, etc. So, it is very useful for their further pharmacokinetics study, their safety assessment and the prediction of the inter-drug interaction associated with them to investigating their influences (induction or inhibition) on CYP 450 enzymes, especially their sex-based differences. By far, the assay of CYP450 and its isoenzymes was used in the selection of novel drugs and the metabolic study in Europe and American, it is also the compulsory test in the novel drug application. In our country, the studies in this filed is still in the beginning stage, but the essentiality and the significant have been realized, so, the studies concerning the metabolic enzymes had been proposed in the latest .This study was carried out by three aspects: in vivo in rats, in vitro in rats and in vitro in human. In each aspect, the study investigated the two marine drug's influences on CYP 1A2, CYP 2E1 and CYP3A4 enzymes, especially their sex-based differences, through comparison of pharmacokinetics data of Caffeine, Chlorzoxazone and Midazolam, which are the special "cocktail" probe drugs for CYP 1A2, CYP 2E1 and CYP3A4, respectively, using the "Cocktail " approach. So, the assessment to the drug's safety and the prediction of inter-drug interactions would be more roundly, as well as a protocol for the design of more suitable drug administration.Caffeine, Chlorzoxazone and Midazolam were demonstrated as the probe drugs of the "Cocktail" approach in the study of effect of 911,971 on CYP 450 subtype enzymes and their sexed-based difference through the assessment of the HPLC experimental method, which includes the selectivity, intraday and inter-day reproducibility, and the detection limits.The results in vivo and in vitro showed that 971 had no effect on CYP 1A2 and CYP3A4 enzymes, either in female or in male subjects; But it had obvious induction effect on CYP 2E1 in male subjects both in vivo and in vitro. The tl/2 P of 971 and control group were 72.43 ± 34.28 min and 271.82 ± 147.86 min ( PO.05 ) respectively in rats in vivo, while the tl/2 of their were 37.04 + 9.61 min and 58.05 + 11.56 min (PO.05) respectively in rats in vitro, as well as 59.35±4.86 and 75.02± 10.89 min (PO.05) respectively in men in vitro. Drug 971 had no obvious effect on CYP2E1 in female subjects. The results in vivo and in vitro confirmed each other.911 had no effect on CYP1A2 enzyme both in male and female rats in vivo; In vitro, 911 had obvious inhibition effect on CYP1A2 in female subjects. The ti/2 of 911 and control group were 31.99+2.78 and 24.31 +2.67min(PO.05)respectively in rats; 91.38±3.72 and 61.21 ±8.09min (PO.05) respectively in men. 911 also had obvious inhibition effect on CYP3A4 enzyme both in male and female rats in vivo. The Un? of female 911 and female control group were 321.65 + 69.05 and 176.55 + 25.40 min(PO.05) respectively, while the t\/2? of male 911 and male control group were 220.42+42.24 and 169.40+22.91 min(PO.05). In vitro, drug 911 showed no effect on CYP3A4 both in rats and human. The results both in vivo and in vitro showed that911 had no effect on CYP2E1. Sometimes, the results of the effect of 91 Ion CYP450 in vivo conflicting its in vitro, it probably related with the differences of drug's chemical structure, the stability of the drug in vivo and in vitro, as well as the decomposition to enzymes.The effects of the drugs on CYP 450 subtype enzymes were different and it was sex-dependent, this sexual difference should be carefully considered when these drugs are used in future experiments. Furthermore, the combined usage of these two drugs with some other drugs, particularly CYP1A2,CYP 2E1 and CYP3A4 involved drugs, should be carefully considered, so as to avoiding the potential toxicity and adverse effects, and offering a more exact safety assessment and a more suitable drug administration.