Our research has demonstrated that
Our research has demonstrated that the absolute bioavailability of oxymatrine, having a similar structure with OSC, was only 6.79±2.52%. About 50% of OSC was converted to its active metabolite SC in vivo; hence, the absolute bioavailability of OSC was speculated to be poor as well . Understanding the disposition of OSC is the first step toward solving a major challenge associated with OSC development. The fast biotransformation of OSC in vivo caused us to hypothesize that first-pass metabolism was the main reason why only 50% OSC was quantifiable in rat plasma in vivo, with substantial amount of SC found in the plasma. Despite that the basic information on bio-efficacy of OSC and SC is readily accessible; the available information on the characterization of the metabolism mechanism is poorly understood. Researchers have recently reported that the formation of SC was rapid. The AUC value of SC was about the same as that of OSC, thus suggesting that SC could also play an important role in the pharmacological action of orally administered OSC , .
In another study, oxymatrine was metabolized into six metabolites as a result of a phase I reaction, including OSC and SC in rats . The available information appears to indicate that OSC may also undergo phase I metabolism, the likely major pathway for its elimination, which is mediated mainly by cytochrome P450 (CYP) enzymes. CYP450 enzymes are significant phase-I drug-metabolizing enzymes used in xenobiotic metabolism and detoxification. They are also involved in the metabolism of more than 90% of all currently available drugs. Up to 90% of human drug metabolism may be attributed to six main enzymes, namely, CYP1A2, 2C8, 2C19, 2D6, 2E1, and 3A4/5. The increased polarity of drugs via CYP metabolism results in their increased water solubility and rapid elimination from the body. However, CYP, which forms a part of the microsomal mixed-function oxidase system, has also been shown to participate in the reduction of several drugs. Particularly, under Florfenicol conditions, CYP has been shown to function in a reductive rather than in an oxidative manner. Examples of substrate reduction include halogenated alkanes, triarylmethanes, nitro compounds, azodyes, and NAPQIs. Preliminary evidence has also suggested the involvement of CYP in the reductive bioactivation of quinones, such as danthron and 1-pipenidinoanthraquinone; CYP2B1 was involved in the one-electron reduction of adriamycin, and nitrofurantoin is metabolized through the CYP450 system .
Materials and methods
Discussion The first aim of this study was to determine the metabolism of OSC by using HLMs and RLMs and the CYP isoforms responsible for the metabolism by using chemical inhibitors and recombinant CYP enzymes. The results showed that the main metabolic pathway of OSC was deoxygenation and had no change on the skeleton of quinolizidine alkaloid compared with the parent compound. OSC was metabolized into at least four metabolites (M0–M3) in rat perfusate, as well as in HLMs and RLMs with NADPH (Fig. 1). The major metabolites were SC, which was over 85% of all the metabolites. Compared with the metabolism in the liver microsome, the reduction rate in intestinal microsome is much lower, which is only about half of that in liver microsome both in humans and rats (Fig. 2C). This observation indicated that the main organ responsible for the metabolism of OSC is the liver. We systematically characterized the effect of specific CYP inhibitors on the metabolism of OSC in the phase I reaction of the human liver and rat liver microsomes to confirm which CYP isoforms were responsible for the metabolism. The results indicated that OSC was mainly metabolized by CYP3A4/5, 2C9, and 2B6 in HLMs, whereas CYP2A and 2D6 played minor roles. However, in rat liver microsomes, the metabolism is slightly different; CYP2A had a stronger effect on the reduction of OSC, which indicated that CYP2A may play a more important role to the OSC metabolism in rat. Moreover, we investigated the OSC metabolism pathways by nine human recombinant CYP isozymes. Our results indicated that the formation of SC was mainly produced by CYP3A5, 3A4, 2B6, 2C9, and 2D6 (Fig. 4), whereas CYP2E1, 2C8, 1A2, and 2C19 did not produce any metabolite. Fig. 8 shows the CYP-mediated metabolic pathways of OSC to SC. The results were comparable to those of the inhibition experiment. The metabolism in human and rat was almost the same, which indicated that rat may be a suitable animal model for the investigation of drug metabolism for OSC.