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  • CYP A and CYP D

    2021-04-08

    CYP3A4/5 and CYP2D6 are among the main drug-metabolizing enzymes in humans that are responsible for the metabolism of more than 50% of marketed drugs [19], [21]. Drugs metabolized by CYPs are prone to drug–drug interactions, thereby modifying their response [18], [32]. Metabolic inhibition is also involved in many drug–drug interactions; in some instances, the drug interactions can be life-threatening for the human body. A life-threatening liver damage can occur when CYP3A inhibitors are co-administrated with terfenadine, astemizole, cisapride, or pimozide [5]. Furthermore, liver damage will happen when CYP2D6 inhibitors are co-administered with codeine and desipramine [8]. The phenotype of CYP2D6 poor metabolizer for CYP2D6 of a patient had major clinical importance in treatment with risperidone because the metabolic pathways are probably inhibited by haloperidol [17]. Less pronounced pharmacokinetic interactions may still be clinically important for drugs, such as oxymatrine (OMT) and OSC with a steep concentration–response relationship or narrow therapeutic index. In addition, if a substrate (e.g., debrisoquine) was mainly metabolized by expressed human CYP2D6, which is an isoform mainly expressed in the human liver, we could also predict that the SLIGKV-NH2 was mainly metabolized in the liver. Our previous studies showed that the absolute bioavailability (F%) of OMT, which has similar chemical structures with OSC, was only 6.79% in rats [22]. Wang et al. [23] reported an interesting phenomenon that when taken orally, most of the OMT was rapidly converted to matrine to a large extent in beagle dogs. Therefore, the similar effects and pharmacokinetics of OSC were expected and considered compared with OMT. Hence, the OSC transformation can be assumed to directly result in the low bioavailability of OSC and can affect the toxicity and efficacy of both OSC and TCM, such as S. flavescens, similar to OMT. Comparing the structures of the two compounds, we tentatively deduced that the OSC may have the similar pharmacokinetic procedure to that of OMT in vivo. The biotransformation of OSC to SC could also result in the low bioavailability of OSC. The toxicological risk of improper usage of S. sophora Root remains very high, specifically in countries such as China, India, and Japan. Sophora Root use is prohibited in Europe because of its high toxicity. However, the mechanism of detoxification is unclear. Based on the electron structure of OMT and MT, OMT was expected to have stronger activity than MT [31]. Both may cause hepatic toxicity, and MT toxicity is greater than OMT [30]. Similarly, we proposed that OSC and SC may have similar phenomenon. Thus, the clarification of the metabolism may be helpful in investigating the TMC toxicity. The combined use of Sophora Root and Astragalus membranaceus is a safe pair in TCM formulation. LD50 levels of Sophora Root decreased to an undetectable value when combined with A. membranaceus in decoction. Furthermore, this mixture has also been reported to process viral myocarditis in humans and rats. Whether A. membranaceus influences the CYP metabolism of quinolizidine alkaloids in vivo or not should be investigated further. Meanwhile, the absorption and metabolism of OSC were also investigated in rat in situ. The hypothesis that first-pass metabolism was the main reason for OSC's poor bioavailability was approved. Whether in vitro or in situ, SC was the main metabolite (over 85% of all the metabolites), and the amount excreted was about equal to the amount of OSC absorbed. The membrane permeability could not be the main problem for OSC poor bioavailability because the total absorbed amount in the four segments was above 75nmol per 30min, which indicated good absorption. There are no significant differences in the permeability of OSC at three concentrations, whereas the absorbed amount of OSC was concentration-dependent. Moreover, intestinal metabolism of OSC was much slower than that of the liver (Fig. 2C). Hence, much of the absorbed OSC was expected to be metabolized upon reaching the liver for phase I transformation, which is consistent with in vivo oral dosing study that showed much phase I metabolite such as SC in rat plasma at a detectable level. According to literature, OMT could be reduced to MT by bacteria. Thus, bacteria existing in intestine may play an important role in the transformation of OSC into SC, which may be another key reason for the poor bioavailability of OSC.