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Santos V, López KJV, Santos LM, Yonamine M, Carmona MJC, Santos SRCJ. Determining plasma morphine levels using GC-MS after solid phase extraction to monitor drug levels in the postoperative period. Clinics. 2008;63:307-14. OBJECTIVE:To implement a selective and sensitive analytical method to quantify morphine in small volumes of plasma by gasliquid chromatography-mass spectrometry (GC-MS), aimed at post-operatively monitoring the drug. METHOD: A gas-liquid chromatographic method with mass detection has been developed to determine morphine concentration in plasma after solid phase extraction. Morphine-d3 was used as an internal standard. Only 0.5 mL of plasma is required for the drug solid-phase extraction in the Bond Elut-Certify ® , followed by the quantification of morphine derivative by GC-MS using a linear temperature program, a capillary fused silica column, and helium as the carrier and make-up gas. The method was applied to determine morphine content in plasma samples of four patients during the postoperative period of cardiac surgery. Patient-controlled analgesia with morphine was performed by a venous catheter, and a series of venous blood samples were collected. After the oroAfter the orotracheal extubation, morphine plasma levels were monitored for up to 36 hours. RESULTS: The run time was 16 minutes because morphine and the internal standard were eluted after 8.8 minutes. The GC-MS method had 0.5 -1000 ng/mL linearity range (r 2 =0.9995), 0.1 ng/mL limit of detection, intraday and interday precision equivalent to 1.9% and 6.8%, and 0.1% and 0.8% systematic error (intraday and interday, respectively). The analytical method showed optimal absolute (98%) and relative (100.7%) recoveries. Morphine dose requirements and plasma levels are discussed. CONCLUSION: The analytical gas-liquid chromatography-mass spectrometry method is selective and adequate for morphine measurements in plasma for applications in clinical studies.

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Following a week of racemic mexiletine HCl at 200 mg tid (2x100 mg capsules), stereoselective aliphatic hydroxylation was studied in eight Chagasic women with chronic ventricular arrhythmias (52-67 yrs) with no history of renal or hepatic diseases. Blood samples were collected at dose interval up to 24 h of drug administration. Plasma concentrations of R(-) and S(+) mexiletine (MEX) and its metabolite hydroxymethylmexiletine (HMM) were determined by HPLC after derivatization with chiral reagent. The differences between R(-) and S(+) enantiomers were compared by paired t-test. Results are mean (95% CI). The following differences (p < 0.05) between R(-) and S(+) enantiomers, respectively, were found: MEX AUCss(0-8) 2.34 (1.84-2.85) vs 2.55 (1.97-3.13) microg.ml(-1) x h(-1); MEX CL/f 11.27 (7.77-14.77) vs 10.46 (7.18-13.74)ml.min(-1).Kg(-1); HMM Cmax 38.26 (24.3-52.22) vs 16.73 (10.1-23.29)ng.ml(-1); HMM Tmax 4.71 (2.67-6.76) vs 3.29 (1.24-5.33) h and HMM AUCss(0-8) 253.50 (165.39-341.61) vs 103.70 (69.51-137.90)ng.ml(-1).h(-1). The AUCss(0-8) ratio R(-)/S(+) for MEX was 0.93 (0.87-0.98) while for HMM was 2.50 (2.16-2.85). Distribution of MEX and HMM enantiomers were not significantly different. In this study we demonstrate that kinetic disposition of mexiletine exhibits stereoselectivity in vivo and that aliphatic hydroxylation is favored for R(-) mexiletine in Chagasic women with ventricular arrhythmias.