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THE EXTRACTION and ANALYSIS of URINARY ANTITUSSIVE METABOLITES USING MEPS™ and ESI-Lcmsn

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THE EXTRACTION and ANALYSIS of URINARY ANTITUSSIVE METABOLITES USING MEPS™ and ESI-Lcmsn TECHNICAL ARTICLE THE EXTRACTION AND ANALYSIS OF URINARY ANTITUSSIVE METABOLITES USING MEPS™ AND ESI-LCMSn Wirth, H.J. Melbourne, Australia, Lahoutifard, N., Courtaboeuf, France, Gooley, A., Melbourne, Australia and Wynne, P.M., Melbourne, Australia. Dr Paul Wynne, SGE Analytical Science, 7 Argent Place, Ringwood, Victoria, 3134, Australia ABSTRACT The MEPS™ consists of a small (~7 µl) compartment, the Microextraction Packed Sorbent (MEPS™) is an adaptation Barrel Insert and Needle Assembly (BIN), that contains the of SPE into a miniaturized device with a typical void volume stationary phase, and is built into the syringe needle. The of less than 10 µL. With operating volumes of this scale and packing material is 40-50 µm silica with 60 Å pore size and its compatibility with autosampler syringes, MEPS™ allows a range of common surface modifications. the specificity of the solid-phase process to be harnessed for digital chromatography using discontinuous changes in solvent polarity. The eluant volumes are sufficiently small to be injected directly into a HPLC system and therefore permit the on-line use of solid-phase extraction methodology in real time with the HPLC. In this application, we describe the analysis of naturally voided human urine samples that were collected following LOAD WASH ELUTE INJECT the administration of single doses of antitussive medicines Figure 2: Standard operation of a MEPS™ extraction containing codeine, dextromethorphan or pentoxyverine. Urine specimens were first hydrolysed with beta- MEPS™ works like other sample preparation tools with glucuronidase and then the analytes of interest were the common steps being sampling, washing and elution extracted using MEPS™ prior to analysis on a Protecol C18 with the difference that the glass syringe design allows HQ105 column using a 1 % v/v aqueous acetic acid – these steps to be performed by a robotic system (such as methanol mobile phase. Detection of the target analytes an autosampler) with the needle being robust enough to was by ESI-MSMS with collision parameters selected for penetrate standard septa. specific analytes. The MEPS™ sorbents were nominally 50 µm silicas modified with C18, C8 or SCX chemistries. ADVANTAGES OF MEPS™ Speculative structural elucidation of metabolites was 3 4 possible by mass fragmentography and MS or MS as • Sample Size and Sensitivity: required. Sample volumes may be as little as 10 µL, or by taking multiple aliquots of 100 µL or 250 µL, samples of 1mL or larger may be concentrated. ™ The effectiveness of MEPS was compared with the same • Robustness: sample prepared off-line using conventional cartridge SPE. Samples can be drawn and dispensed through septa. The method was used to demonstrate the effectiveness of • Automation: ™ The capability to extract samples and make injections on-line MEPS for on-line extraction of biological fluids for LCMS using a single device reduces both sample processing times and analysis. the need for operator intervention. • Sorbent Life: THE MEPS™ PRINCIPLE Typical BIN life for extraction of whole plasma sample is conservatively about 40 to 100 samples. This significantly increases for cleaner samples. • Carry Over: The small quantity of phase in the MEPS™ BIN can be easily and effectively washed between samples to reduce the possibility of G carryover. This washing process is simply not practical with off-line F ™ E SPE devices. With automation of MEPS washing can occur while the A Needle D B Plug previous sample is running. C B C Screen Flexible and easy to use: D Sorbent • A E Sorbent Capsule The dimensions of the sorbent bed ensure that the performance F Seal G Shank remains identical to conventional SPE devices when used for extraction of similar samples. Figure 1: The MEPS™ catridge www.sge.com TECHNICAL ARTICLE EXPERIMENTAL Chromatographic Conditions and Detection Column: SGE ProteCol™-P C18 HQ105 Administration and Sample Collection 150 mm x 4.6 mm ID Oral administration of a single dose of: 10 mL Vicks Cough Mobile Phase A: 1 % aq. acetic acid in 10 % methanol Syrup (equivalent to pentoxyverine (carbetapentane) Mobile Phase B: 1 % aq. acetic acid in 90 % methanol citrate 15 mg), 10 mL Robitussin DX Dry Cough Forte syrup Flow rate: 0.7 ml/min (equivalent to 30 mg dextromethorphan hydrobromide) 2 Gradient: 20 min 0 to 100 % B Mersyndol day strength tablets (equivalent to paracetamol 10 min at 100 % B 1000 mg and codeine phosphate 19.2 mg) Naturally Temperature: 40 °C voided urine samples were collected at 0, 2, 3 and 4 hours Injection volume: 10 µL following administration. Urine samples were stored frozen Detection: Thermo LCQ Classic positive ion mode at -20 °C until required for analysis. SAMPLE 1: DEXTROMETHORPHAN AND ITS Sample preparations METABOLITES 3 mL aliquots of urine from the samples collected at 0 and 2 hours after oral administration were diluted with 0.1 M Pharmacokinetics (http://www.tga.gov.au/npmeds/pi-dex- phosphate buffer (pH 6.0, 4.5 mL) and the pH adjusted to tromethorphan.rtf): Dextromethorphan is well absorbed 6.2-6.3. The samples were then enzyme hydrolysed with from the gastrointestinal tract after oral administration. It is beta-glucuronidase for 2 hours at 50 °C. Samples were metabolised in the liver, exhibiting polymorphic metabolism extracted by either a conventional mixed mode SPE method involving the cytochrome P450 isoenzyme (CYP 2D6). It is or by a reversed-phase MEPS™ method. excreted in the urine as unchanged dextromethorphan and demethylated metabolites, including dextrorphan, which SPE extraction was performed on Bond-Elut Certify™ has some cough suppressant activity. The plasma elimina- columns using methods described previously. (Wynne PM, tion half-life of dextromethorphan is 1.2 to 3.9 hours. Batty DC, Vine JH and Simpson NKJ., Chromatographia, 59 (4/5), S50-S61, (2004)). 1.2E+07 MEPS™ ™ ™ 1.0E+07 MEPS extraction was performed on C18 MEPS BINS fitted 6E+06 to a 100 µL MEPS™ syringe. MEPS™ BINS were conditioned 271.99 sequentially with 50 µl methanol and 100 µl water. 8.0E+06 2.5E+06 240 250 260 270 280 290 6.0E+06 288.00 • 50 µL methanol conditioning • 100 µL water conditioning 4.0E+06 240 250 260 270 280 290 • 1 mL sample was drawn and expelled in 80 µl steps 2.0E+06 • 80 µL water wash * * 0E+00 * • 50 µL sodium tetraborate pH adjustment 0 5 10* 15 20 25 30 • 80 µl water wash 1.8E+06 5E+06 258.06 H-N O-CH • 2 x 80 µL air drying 3 • 2 x 20 µL methanol elution 1E+07 240 260 280 300 3E+06 CH • 10 µl iso-propanol elution 3 H-N 2E+07 272.06 O-CH Cytochrome P450 3A4 Cytochrome P450 2D6 3 Dextromethorphan ™ (parent compound) Mixed Mode MEPS for codeine and metabolites 2E+07 240 250 260 270 280 290 3E+07 1.8E+06 ? CH ™ 3 OH H-N H-N MEPS extraction was performed on M1 (C8/SCX mixed CH 3 H-N OH OH 3E+07 mode) MEPS™ BINS. The extractions were the same as for OH Dextrorphan (active drug) 244.09 274.00 258.13 SPE 240 250 260 270 240 250 260 270 280 290 the C18 extractions except for the following: pH adjustment 3E+07 with 50 µl 1 % v/v acetic acid, elution with 100 µl methanol followed by 20 µl 1 % v/v ammonia in methanol. Metabolites of Dextromethorphan www.sge.com TECHNICAL ARTICLE SAMPLE 2: CARBETAPENTANE AND ITS METABOLITES 5.0E+06 3.5E+05 HO 4 1 ™ 286.08 MEPS 4.5E+06 N CH III O 3 H HO Carbetapentane exhibits a 4.0E+06 Morphine (M=285.34) R5 270 280 290 300 310 320 complex metabolite pattern 3.5E+06 1.6E+06 O H C 3 2 R4 = R1 where R1 and R2 are either 3.0E+06 N HO C-OCH22 CH OCH 22 CH -N O R2 OH HO ethyl groups or hydrogens 2.5E+06 Hydroxycodeine (M=285.34) R3 270 280 290 300 310 320 and R3 to R5 are either hy- 2.0E+06 drogens or hydroxy groups. 1.5E+06 5 1.0E+06 6E+06 1 hydroxy metabolite (M+1=350) O 5.0E+05 2,3 = 1 2 hydroxy desethyl metabolite (M+1=322) CH25 3 hydroxy metabolite (M+1=350) C-OCHCHOCHCH-N22 22 (#14: M+1=334) CH 4 dihydroxy metabolite (M+1=366) 25 0.0E+00 5 dihydroxy desethyl metabolite (M+1=348) 0 5 10 15 20 25 30 5E+06 ™ 6 dihydroxy metabolite (M+1=366) 14 MEPS 7 hydroxy desethyl metabolite (M+1=348) 8 hydroxy metabolite (M+1=350) 5.0E+05 1.6E+06 H C 9 hydroxy metabolite (M+1=350) 3 3 10 dihydroxy metabolite (M+1=366) 4E+06 O N CH3 11 hydroxy metabolite (M+1=350) HO 1.0E+06 H 12 didesethyl metabolite (M+1=278) HO 13 desethyl metabolite (M+1=306) Hydroxycodeine (M=285.34) 14 parent (M+1=334) 3E+06 15 hydroxy metabolite or possible N-oxide (M+1=350) 1.5E+06 270 280 290 300 310 320 6E+06 H C 3 4 2.0E+06 O N CH3 2E+06 8 H HO 2 Codeine (M=285.34) 2.5E+06 15 3 270 280 290 300 310 320 1E+06 13 1.6E+06 1 6 int.Std. 4,5 3.0E+06 H C 3 5 12 7 286.03 9 10 11 O N HO 0E+00 3.5E+06 H Signals are related to HO SPE 10 11 12 13 14 15 16 17 18 19 20 Norcodeine (M=285.34) carbetapentane which was 270 280 290 300 310 320 4.0E+06 co-administrated 1E+06 9 11 12 5 7 10 int.Std.
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