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Simultaneous Determination of Various Macrolides by Liquid Chromatography/Mass Spectrometry Youn-Hwan Hwang, Jong-Hwan Lim, Byung-Kwon Park and Hyo-In Yun*

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Simultaneous Determination of Various Macrolides by Liquid Chromatography/Mass Spectrometry Youn-Hwan Hwang, Jong-Hwan Lim, Byung-Kwon Park and Hyo-In Yun* J. Vet. Sci. (2002), 3(2), 103-108 J O U R N A L O F Veterinary Science Simultaneous Determination of Various Macrolides by Liquid Chromatography/Mass Spectrometry Youn-Hwan Hwang, Jong-Hwan Lim, Byung-Kwon Park and Hyo-In Yun* Division of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Chungnam National University Received J a n . 4, 2002 / Accept ed Ap r . 29, 2002 ABSTRACT7) poultry, those are 0.125 g/kg for erythromycin and 0.1 g/kg for tylosin. In order to monitor macrolide residues, simple, Macrolides are frequently use d in veterinary confirmatory and simultaneous analytical methods are m edicine as therape utic and preve ntive agents for required. various diseases. It is difficult to determine m acrolides Microbiological assays were widely used for determination sim ultaneously w ith conventional m ethods due to of macrolide antibiotics [3, 4]. Unfortunately, these methods their sim ilar structures. A sim ultaneous analysis for could not be used for simultaneous analysis due to lacks of erythrom ycin, roxithrom ycin, tiam ulin and tylosin their specificities. Gas chromatography-mass spectrometry w ith LC/MS has bee n develope d. Se paration w as (GC-MS) supplies good sensitivity and selectivity [5], but pe rform ed on C18 reversed phase colum n. Mobile direct analysis for macrolides antibiotics is difficult because phase w as gradiently flow e d w ith 10 m M am m onium of their thermal labile property and low volatility. acetate and m ethanol. The m ass spectrome ter w as Liquid chromatographic methods have been reported for run in the positive m ode and sele ctive ion monitoring the determination of macrolide antibiotics: UV absorption m ode. The m olecular ions w ere [M+H]+ form at m /z [6-11], fluorimeteric [12-14], ch em ilu m in escen ce [15] a n d 837.5 for erythromycin, at m/z 859.5 for roxithrom ycin, elect r och em ica l det ection [16, 17] m et h ods h a ve been u sed at m /z 494.2 for tiam ulin and at m/z 916.7 for tylosin. for det erm in a tion , bu t t h ese m et h ods h a ve sh ow n h igh Lim its of detection w ere in the range from 0.001 to lim it s of d et ect ion . 0.01 ㎍/g low er than their MRLs. Recently, several simultaneous determination methods of macrolide antibiotics have been developed by mass Keyw ards : simultaneous determination; liquid chromato- spectrometry coupled with HPLC [18-20]. The determination graphy/mass spectrometry; macrolides antibiotics methods of macrolides by LC/MS have advantages such as high specificity and selectivity due to each molecular mass. 1. Introduction The aim of this study is to develop a more simple, rapid and effective method for the simultaneous determination of Macrolide antibiotics have 12-, 14-, 16- or 17-membered three macrolide antibiotics (erythromycin, roxithromycin macrocyclic lactone ring, which is bound to several amino and tylosin) and a pleuromultlin antibiotic (tiamulin) by and/or neutral sugars (fig.. 1). Because of their effective LC/MS with electrospray interface. Although tiamulin does antimicrobial activity against Gr am-posit ive bacteria, my- not belong to a group of macrolide antibiotics, we coplasma, chlamydia, they are frequently used in industrial determined this drug due to its similar structure to tylosin. animals to treat and prevent diseases or as growth promotants [1]. 2. Materials and methods Incorrect use of these antibiotics may leave residues in edible tissues causing toxic effects on consumers, e.g., 2-1 Che micals and reagents allergic reactions in hypersensitive individuals, or indirectly, Erythromycin, roxithromycin and tylosin were supplied problems through the induction of resistant strains of by S in il Ch em ica ls (Seou l, Kor ea ). Tia m u lin w a s su pplied by bacteria [2]. Therefore, the Sourth Korea has set maximum Da esu n g M icr obia ls (Seou l, K or ea ). H P LC gr a d e w a t er a n d residue limits (MRLs) for macrolide antibiotics in edible m et h a n ol w er e pu rch a sed fr om J .T. & Ba k er (N ew J er sey, tissues of food-producing animals. The MRLs of erythromycin U SA). Rea gen t gr a de a m m on iu m a ceta te w a s pu r ch a sed and tylosin are 0.1 g/kg in bovine and porcine. In case of fr om S igm a (Missou ri, U SA). Th e in dividu a l stock sta n d a r d solu t ion s w er e p repa r ed a s ＊Corresponding author: Hyo-In Yun 1 m g/㎖ in methanol and working standard solutions were Tel: +82-42-821-6759 Fax: +82-42-822-5780 prepared weekly by dilution of stock standard solutions with E-mail: [email protected] 104 Youn-Hwan Hwang, Jong-Hwan Lim, Byung-Kwon Park and Hyo-In Yun Fig. 1. The structure of erythromycin (A), roxithromycin (B), tylosin (C) and tiamulin (D). m eth a n ol. All st a n da r d solu t ion s w er e st ored a t 4℃ and range of 0.001 ㎍/㎖ ~ 5 ㎍/㎖. were stable for at least 1 month under this condition. Limit of detection (LOD) and limit of quantitation (LOQ) Deionized or distilled water of 18.2 ㏁ cm-1 resistivity was were based on the signal-to-noise ratio based on their areas. used throughout the experiment. The signal-to-noise ratio of 3 was accepted for the LOD and that of 10 for the LOQ. 2-2 Instrumentation and chromatographic conditions Samples were analyzed by a Hewlett-Packard 1100 series 3. Results LC/MSD system. It consisted of a G1322A degasser, a G1312A binary pump, a G1315A photo-diode-array detector, 3-1. Chrom atographic separation a 59987A electrospray interface and a 5989B mass spectrometer. All drugs used for the experiment were separated under The separation was performed on Nova-Pak C18 reverse the adopted conditions within 18 min (Fig. 2). Each phase column (4 ㎛, 3.9 mm x 150 mm I.D., Waters, USA). separation of erythromycin (15 min), roxithromycin (16 Analytical system was operated with a gradient elution at min), tylosin (12 min) and tiamulin (14 min) was achieved flow rate of 0.5 ㎖/min. The mobile phase consisted of 10 successfully, on the same chromatogram. mM ammonium acetate (A) and methanol (B). Gradient runs were programmed as follows: 100% B for 3 min, 3-2. Mass spectra decrease from 100% to 90% B for 6 min, decrease from 90% For each molecule, the produced ions on mass spectra to 5% B for 6 min, 5% B for 5 min, re-equilibration with were the molecular related ion [M+H]+, two adduct ions 100% B for 5 min, post-run with 100% B for 10 min, until [M+Na]+ and [M+K]+, and several fragmentation ions (Fig. the next sample injection. 3). The molecular ions, [M+H]+, at m / z 734.5, 837.5, 494.4 The nebulizer gas was flowed at 45 p.s.i., 350℃ and 9.0 and 916.5 for erythromycin, roxithromycin, tiamulin and l/min and quadrupole was heated to 100℃. Mass spectrometer tylosin were represented dominantly. Except tiamulin, other was run in the positive mode and scan mode from m/z 100 drugs produced two adduct ions, [M+Na]+ and [M+K]+, at to 1000. Fragmentation voltage was 100 V. Analysis was m/ z 756.5 and 772.5 for erythromycin, at m/ z 859.5 and carried out at the room temperature. 875.5 for roxithromycin, at m/ z 938.5 and 954.5 for tyloisin (Fig. 3). The appearance of fragmentation ions was due to 2-3 Calibration curve s and the limit of de tection the dissociation of amino or sugar moieties on the structure Calibration curves have been constructed by plotting area of drugs. The m / z 576.5 and 679.5 in mass spectra of against the standard concentrations of macrolides in the erythromycin and roxithromycin were corresponding with Simultaneous Determination of Various Macrolides by Liquid Chromatography/Mass Spectrometry 105 F ig . 2. Tot a l ion ch rom a togra ph y (TIC, A) of m a crolide a n d t ia m u lin . E xt ra ct ion s ch r om a t ogr a ph y (E IC) of tia m u lin (B), t ylosin (C), er yth r om ycin (D) a n d r oxit h rom ycin (E ). a [M-desosamine+H]+. The m / z 158.1 of erythromycin and wit h pr e-colu m n deriva tiza tion pr ocedu r es r equ ires lon g roxithromycin was corresponding with a [desosamine + H]+, sep a r a t ion t im es a n d is less sen sit ive t h a n LC/MS [12-14]. and the m/ z 115.1 of roxithromycin was corresponding with In a ddition, fluorim etric detection is lim ited for sim u lt a n eou s a [cladinose-OCH3 + H]+. The fragment ions of tiamulin, det er m in t ion beca u se of t h e differen t der iva t iza t ion m et h od m/ z 192.1 was a moiety of [2-(diethylamino)-ethyl, thio] of ea ch dr u g.
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