A sensitive and selective liquid chromatographic tandem mass spectrometric method was developed and validated for the determination of sinomenine in human plasma. Plasma samples were precipitated using methanol with metronidazole as internal standard. Separation was carried out on an Inertsil ODS-3 column using a mixture of 0.2% ammonium acetate solution (A) and methanol (B) as the mobile phase with linear gradient elution as follows: 0 min (50%B)→1.5 min (80%B)→4.5 min (80%B)→4.6 min (50%B)→6.0 min (50%B). All mass data were obtained in the positive ion mode, and the fragmentation transitions for the selective multiple reaction monitoring were m/z 330→181 and 172→128 for sinomenine and metronidazole, respectively. The method was fully validated to be accurate and precise with a linear range of 0.5-500 ng/mL and applied to a single- and multiple-dose pharmacokinetics study of sustained-release capsules of sinomenine hydrochloride in 20 healthy Chinese volunteers. After oral administration of a single 60-mg dose, the T(max), C(max), AUC(0-96) and t(1/2) were 7.9±2.0h, 123±22 ng/mL, 3032±682 ng h/mL and 13.4±1.6 h, respectively. After oral administration of the 60 mg capsules twice-daily for 7 consecutive days, these parameters were 4.4±3.6 h, 279±69 ng/mL, 7333±2096 ng h/mL and 15.1±1.3 h, respectively. The AUC and C(max) values after multiple-dose treatment were significantly higher than those after a single-dose treatment (P<0.01), with an accumulation factor of 2.49±0.77.
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