Influence of Co-Administrated Sinomenine on Pharmacokinetic
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Journal of Ethnopharmacology 99 (2005) 61–67 Influence of co-administrated sinomenine on pharmacokinetic fate of paeoniflorin in unrestrained conscious rats Zhong Qiu Liu a, Hua Zhou a, Liang Liu a, Zhi Hong Jiang a, Yuen Fan Wong a, Ying Xie a, Xiong Cai a, Hong Xi Xu b, Kelvin Chan a, ∗ a School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong, PR China b Hong Kong Jockey Club Institute of Chinese Medicine Limited, Hong Kong, PR China Received 10 August 2004; accepted 26 January 2005 Available online 20 March 2005 Abstract Paeonia lactiflora Pall. (Ranunculaceae) root and Sinomenium acutum Rehder and Wilson (Menispermaceae) stem are two herbs widely used in Chinese medicine to treat rheumatoid arthritis. While, in theory, either herb could be used alone, in practice, Chinese medicine practitioners prescribe them together. Studies on pharmacokinetic interaction between the active constituents of these two herbs (paeoniflorin and sinomenine, respectively) provide empirical evidence to support their clinical practice. A single dose of paeoniflorin (150 mg/kg) alone and with sinomenine hydrochloride (90 mg/kg) was administered by gastric gavage to unrestrained conscious male Sprague–Dawley rats (n =6, 250–300 g). Blood samples were collected periodically via a jugular vein before and after dosing from 10 min to 12 h. A high-performance liquid chromatographic (HPLC) assay was developed to determine the plasma concentrations of paeoniflorin. Non-compartmental pharmacokinetic profiles were constructed by using the software PK Solutions 2.0. The pharmacokinetic parameters were compared using unpaired Student t-test. After co-administration of sinomenine, the peak plasma concentration of paeoniflorin was elevated (P < 0.01), the peak time was delayed (P < 0.01), the AUC0–t was increased (P < 0.001), the mean residence time (MRT) was prolonged (P < 0.01), the CL was decreased (P < 0.01) and the Vd was reduced (P < 0.05). These results indicate that sinomenine hydrochloride at 90 mg/kg significantly improved the bioavailability of paeoniflorin in rats. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Paeoniflorin; Sinomenine; Rheumatoid arthritis; Pharmacokinetics; Bioavailability 1. Introduction tered orally. This is probably due to limited transportation of paeoniflorin across the gastrointestinal mucosa (Takeda et Paeoniflorin is a bioactive monoterpene glucoside (Fig. 1) al., 1995, 1997). In Mainland China, the total glucosides of presenting in the root of Paeonia lactiflora Pall. (family Ra- Paeonia lactiflora Pall. (TGP) comprising more than 70% of nunculaceae), which has been widely used to treat inflam- paeoniflorin, has been approved by the State Food and Drugs mation and arthritic conditions according to the traditional Administration of China for the clinical application in treat- Chinese medical system. The therapeutic effects of the herb ing rheumatic and arthritic diseases as a patented botanical and its active component, paeoniflorin, have been confirmed drug (Zhao et al., 1997). While the drug is useful, neverthe- by experimental pharmacological investigations (Takagi and less, the low bioavailability of paeoniflorin might be restrict- Harada, 1969a,b). However, previous pharmacokinetic stud- ing its therapeutic efficacy. Therefore, this investigation aims ies have shown that paeoniflorin has a poor absorption rate, to use the pharmacokinetic profile of paeoniflorin to find a and thus a very low bioavailability (3–4%) when adminis- way to improve its bioavailability and thereby enhance its therapeutic efficacy. ∗ Corresponding author. Tel.: +852 3411 5308; fax: +852 3411 5317. In treating arthritis, Chinese medicine practitioners usu- E-mail address: [email protected] (K. Chan). ally include both the root of Paeonia lactiflora and the 0378-8741/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jep.2005.01.052 62 Z.Q. Liuet al. / Journalof Ethnopharmacology 99 (2005) 61–67 Nomenclature AUC0–∞ area under concentration–time curve from zero up to infinite time AUC0–t area under concentration–time curve from zero up to a definite time t CL total clearance Cmax maximum plasma concentration Frel relative bioavailability HPLC high-performance liquid chromatography MRT mean residence time R.S.D. relative standard deviation Fig. 2. Chemical structure of sinomenine. t1/2 A phase half-life of absorption phase t1/2 D/A phase half-life of distribution phase t1/2 E phase half-life of elimination phase gies in adjuvant arthritis rats (Liu et al., 1999). Studies on the tmax time to reach maximum plasma concentration pharmacokinetics of sinomenine using technologies of mi- TGP total glucosides of Paeonia lactiflora Pall. crodialysis and a hepato-duodenal shunt probe in rats demon- Vd volume of distribution strated that sinomenine undergoes active hepatobiliary elimi- nation; this process might be regulated by P-glycoprotein and probably involves P450 (Tsai and Wu, 2003). Therefore, in the present study we chose to investigate the possible influ- stem of Sinomenium acutum Rehder and Wilson (fam- ences of sinomenine on paeoniflorin by pharmacokinetics to ily Menispermaceae) in their medical prescriptions. This see if interaction between these two constituents was respon- clinical practice suggests that there might be synergic sible for the enhancement observed in using the two herbs effects between the herbs (Wong and Wu, 1936). Pre- together in clinical practice. vious work on the Chinese medicinal herb Sinomenium acutum demonstrated that the alkaloid sinomenine is one of the main active components of the plant (Tai and 2. Materials and methods Hopkins, 1998). Sinomenine (7,8-didehydro-4-hydroxy-3,7- dimethoxy-17-methylmorphinan-6-one; Fig. 2) has been 2.1. High-performance liquid chromatography analysis demonstrated to significantly inhibit inflammatory reactions caused by various phlogistic agents (Irino, 1958; Cheng et The HPLC system consisted of an Agilent quater- al., 1964; Huo and Che, 1989). The therapeutic efficacy of nary HPLC model HP 1100 series (Hewlett-Packard, Palo sinomenine was also confirmed in patients with rheumatoid Alto, CA, USA), fitted with an Altima C18 column arthritis (Ke and Xiu, 1986; Shi et al., 1986). Studies in our (250 mm × 4.5 mm, 5 m). The mobile phase used was wa- previous work have revealed that the alkaloid has marked ter:acetonitrile (86:14), filtered through a 0.45 m Millipore effects in inhibiting the proliferation of mouse spleen cells, filter (Millipore, Hong Kong). The flow-rate was maintained human peripheral blood mononuclear cells as well as rat syn- at 1 ml/min, and the detection was performed at a wavelength ovial fibroblasts, the synthesis of proinflammatory mediators of 231 nm under constant temperature (25 ± 0.1 ◦C). of prostaglandin E2 and leukotriene C4 and the production of nitric oxide by macrophages (Liu et al., 1994a,b, 1999). It has 2.2. Chemicals also been shown to significantly ameliorate arthritic patholo- The reference standards of paeoniflorin and sinomenine hydrochloride (≥98%) were purchased from the State Insti- tute for the Control of Pharmaceutical and Biological Prod- ucts of China. Pentoxifylline, the internal standard for paeoni- florin, was purchased from Sigma (St. Louis, MO, USA). Acetonitrile and perchloric acid were obtained from Merck (Darmstadt, Germany). 2.3. Animals Male Sprague–Dawley rats weighing 250–300 g were pur- chased from the Laboratory Animal Services Center of the Fig. 1. Chemical structure of paeoniflorin. Chinese University of Hong Kong. The animals were housed Z.Q. Liuet al. / Journalof Ethnopharmacology 99 (2005) 61–67 63 in different cages (five animals per cage) and acclimated in replaced by a collection syringe the desired amount (0.2 ml) the laboratory for at least one-week prior to testing. Before of blood was taken. Next, the collection syringe was removed experiments the animals were fasted for 12 h with water ad and replaced with a heparinized syringe. Blood was gently libitum, and maintained at 21 ◦C temperature with 60% rela- rinsed from the catheter by flushing with the same volume of tive humidity and a 12 h light/12 h dark cycle. After surgery, heparinized saline (20 units/ml) to replace the loss volume of rats were housed individually in metabolite cages for one- blood a plug was inserted in the catheter. Finally, the blood week recovery and underwent pharmacokinetic treatment ac- was expelled from the collection syringe into a heparinized cording to a jugular-catheterized rat model (Thrivikraman et 1.5 ml micro-centrifuge tube. al., 2002). All procedures involving animals and their care In each of the experiments, one rat was administered were carried out according to the regulations of the Com- with paeoniflorin alone, while another was administered mittee on the Use of Human & Animal Subjects in Teach- with paeoniflorin plus sinomenine hydrochloride. Both com- ing and Research of Hong Kong Baptist University and pounds were prepared as an aqueous solution and admin- Health Department of Hong Kong Special Administrative istered orally to the fasted rats. For the co-administration Region. protocol, paeoniflorin was first administered at the dosage of 150 mg/kg body weight, and then, immediately following, 2.4. Surgery sinomenine was administered at the dosage of 90 mg/kg body weight. Silicone medical grade tubing 100 mm long (Silastic Cat. After administration, jugular vein blood samples were col- No. 602-155; Dow Corning, Midland, MI, USA) with two lected (0.2 ml) from the rats into heparinized 1.5 ml micro- stoppers made of medical adhesive silicone (Silastic Cat. No. centrifuge tubes at the following time intervals: 0, 10, 20, 801; Dow Corning) was used. For insertion of the catheter in 30, 45, 60, 80, 100, 120, 150, 180, 240, 300, 360, 540 and the sinus venosus, the length of the tip of the catheter to the 720 min. Data from these samples were used to construct first stopper was set at 26 mm (Harms and Ojeda, 1974). pharmacokinetic profiles by plotting drug concentrations ver- Rats were anesthetized by intraperitoneal administration sus times.