Investigation The Effect Of Zolmitriptan On CYP3A Activity In Rats Liver

Cytochrome P450 (CYPs) constitute a superfamily of isoforms that play an important role in the metabolism of drugs. CYP450 exists mainly in liver. One of the important aspects of the CYP is that some of the enzymes can be induced by many drugs and compounds. When drugs are administered concurrently, drug interactions can also occur as a result of the induction of CYPs. Induction of P450s enzymes can alter intestinal and hepatic clearance of drugs and consequently the serum levels of drugs that are metabolized by these enzyme systems. Induction undoubtedly contributes to interindividual and intraindividual variation in drug response and can cause drug-drug interactions. Drugs given concomitantly with other drugs have the potential to cause inefficacy of drug treatment or pharmacological toxicity. CYP3A is the most abundant CYP isoform, and play a very important role in drug metabolism and mainly localized on the liver and intestine. CYP3A has abroad substrates, it can metabolism more than 50% of clinical drugs. CYP3A appears to be a key enzyme in drug-drug interactions. Zolmitriptan is used as an acute oral treatment for migraine. It was reported that potential drug interactions can take place in clinic when zolmitriptan was administered concurrently with some other drugs. Therefore, this paper has investigated the induction effect of zolmitriptan on liver CYP3A. This research can provide some scientific evidences in clinical medication.Part one: In vivo investigation of the induction effect of zolmitriptan on liver CYP3A.To study the effect of zolmitriptan on the expression of cytochrome P450 in rat liver after the rat was treated with zomitriptan. After the rats induced by zolmitriptan, we using testosterone and nifedipine as probe substrates and in vitro incubation as metabolism method to determine the change of CYP3A activity. At the same time, we also used RT-PCR to evaluate the degree of mRNA of CYP3A1/CYP3A2 in zolmitriptan pretreated rats liver. In another side, we using midazolam as a CYP3A in vivo probe substrates. The rats treated with zolmitriptan and then intravenous injected midazolam in trail. Then we analyzed the pharmacokinetic parameters of the investigation. We found that the male rat liver microsome induced with zolmitriptan, as that induced with dexmethasone, can potently metabolize testosterone and nifedipine, and significantly different from blank control. However, the female rat liver microsome induced with zolmitriptan metabolized probe substrates as blank control, had no significantly increase in CYP3A enzyme activity. The result from RT-PCR shows that both of the expression level of CYP3A1 and CYP3A2 mRNA was significantly improved in male rat liver induced by zolmitriptan, but not improved in female rat liver pretreated by zolmitriptan. The results of the pharmacokinetics of the in vivo probe substrate were consistent with front experiments. The area under the clearance (AUC) and the elimination half-life (ti/2) of midazolam was significantly reduced in male rats by the zolmitriptan and dexamethasone pretreatment. While in female rats there were no significantly changes. The result was consistent with the consequence of microsome incubation and RT-PCR.Part tow: In vitro investigation of the induction effect of zolmitriptan on liver CYP3A enzyme. In part one we study the induction of zolmitriptan in vivo. In order to exclude the possibility of the influence of various in vivo factors, we induced hepatocte with zolmitriptan to investigate the activity of CYP3A enzyme. Primary hepatocytes culture is a perfect model for toxicological and pharmacological studies, and commonly used to evaluate CYP induction. Therefore, we also used primary rat hepatocytes cultures to study the induce effect of zolmitriptan on CYP3A enzyme. Hepatocytes were isolated from male or female SD- rats by a modification of the previously described two-step collagenase digestion method. The monolayer hepatocytes cultures treated with zolmitriptan for 24h, and determine the CYP3A enzyme activity with probe substrate testosterone. The metabolism of probe substrate in male or female hepatocytes treated withzolmitriptan have no significant different from control. As the same results, there was no significantly improved of CYP3A1 and CYP3A2 mRNA in male rat hepatocytes pretreated by zolmitriptan.From the results of the two parts, we can conclude that zolmitriptan in vivo can selectly induce male rat liver CYP3A enzyme, and no induction effect on female rat liver CYP3A enzyme. Due to the in vivo gender-different regulation, zolmitriptan can induce the expression of CYP3A enzyme in male rats and the induction effect is gender-difference.