Drugs and Poisons in Humans - A Handbook of Practical Analysis (Part 33)

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Drugs and Poisons in Humans - A Handbook of Practical Analysis (Part 33)

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Introduction: Diphenylmethane antihistaminics are being widely used for treatments of allergy, motion (travel) sickness and cold. They are also being sold as over-the-counter drugs. The structures of principal drugs of this group are shown in Figure 1.1. They are being analyzed by GC [1–6] and HPLC [7–13]. In this chapter, a GC method for simultaneous analysis of diphenylmethane antihistaminics and also HPLC methods for some representative drugs of this group are presented.

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  1. 4.1 II.4.1 Diphenylmethane antihistaminics by Yoko Hieda and Kojiro Kimura Introduction Diphenylmethane antihistaminics are being widely used for treatments of allergy, motion (travel) sickness and cold. They are also being sold as over-the-counter drugs. The structures of principal drugs of this group are shown in > Figure 1.1. They are being analyzed by GC [1–6] and HPLC [7–13]. In this chapter, a GC method for simultaneous analysis of diphenylmethane antihistaminics and also HPLC methods for some representative drugs of this group are pre- sented. Simultaneous analysis by GC [4] Reagents and their preparation • Diphenhydramine hydrochloride, diphenylpyraline hydrochloride, phenyltoloxamine citrate, orphenadrine hydrochloride, benactyzine hydrochloride, doxylamine succinate, carbinoxamine maleate, chlorpheniramine maleate, triprolidine hydrochloride, homo- chlorcyclizine dihydrochloride, hydroxyzine dihydrochloride, clemastine fumarate and meclizine dihydrochloride can be purchased from Sigma (St. Louis, MO, USA). Pure powder of terodiline hydrochloride and piperilate hydrochloride was donated by Kissei Pharmaceutical Co., Ltd., Nagano, Japan and Nippon Shinyaku Co., Ltd., Kyoto, Japan, respectively. Sep-Pak C18 cartridges (classic type) were purchased from Waters (Milford, MA, USA). Other common chemicals were of the highest purity commercially available. • Care should be taken for that all of the above 15 kinds of drugs are in the salt forms. All compounds (5-mg each as the weight of its free base) are altogether dissolved in methanol to prepare 10 mL solution; a 10-µL volume of the mixture solution is spiked into 1 mL of whole blood or urine. One of the 15 drugs is selected for use as internal standard (IS). • Chloroform/methanol (9:1) and distilled water, 100–200 mL each, are prepared. • 0.5 M NaHCO3 solution: a 4.2-g aliquot of NaHCO3 is dissolved in distilled water to pre- pare 100 mL solution. GC conditions GC columna: DB-1 (15 m × 0.32 mm i. d., film thickness 1.0 µm), DB-17 (15 m × 0.32 mm i. d., film thickness 0.25 µm) both obtained from J & W Scientific (Folsom, CA, USA). © Springer-Verlag Berlin Heidelberg 2005
  2. 316 Diphenylmethane antihistaminics ⊡ Figure 1.1 Structures of principal diphenylmethane antihistaminics. GC conditions: an HP 5890 Series II gas chromatographb (Agilent Technologies, Palo Alto, CA, USA); detector: FID; column temperatures: 160 °C (1 min) →5 °C/min →290 °C for the DB-1 column, and 160 °C (1 min) →5 °C/min →280 °C for the DB-17 column; injection tem- perature: 240 °C; detection temperature: 280 °C; carrier gas: He; its flow rate: 3 mL/min; a 1-µL aliquot of sample solution is injected into GC in the splitless mode (1 min), followed by the split mode at 160 °C of oven temperature.
  3. Simultaneous analysis by GC 317 Procedure i. A 10-mL volume of methanol and 10 mL distilled water are passed through a Sep-Pak C18 cartridge c for its activation. ii. A 10-µL aliquot of methanolic solution of a suitable ISd (in case of simultaneous analysis of spiked drugs, 5 µg each in the 10 µL solution) is added to 1 mL whole blood, and mixed well with 9 mL distilled water for complete hemolysis. To this mixture, 5 mL of 0.5 M NaH- CO3 solution is added to make it slightly alkaline. To 1-mL volume of a urine specimen, a 10-µL aliquot of the IS solution, 4 mL distilled water and 5 mL of 0.5 M NaHCO3 solution are added. iii. Either mixture of whole blood or urine specimen is poured e into the activated cartridge with a flow rate not faster than 5 mL/min using a 10-mL volume glass syringe. iv. The cartridge is washed with 10 mL distilled water, and the target compounds are slowly eluted with 3 mL of chloroform/methanol (9:1) into 4-mL volume glass vial. v. A small amount of the upper aqueous phase of the eluate is carefully removed with a Pas- teur pipette; the lower organic phase is evaporated to dryness under a stream of nitrogen. The residue is dissolved in 100 µL methanol, and a 1-µL aliquot of it is injected into GC. For quantitation, the peak area ratio of a target compound to IS is obtained. vi. For quantitative analysis, a 10-µL of IS solution and one of various concentrations of a target compound are added to 1 mL of blank whole blood or urine obtained from healthy subjects; at least 4 vials containing different concentrations of the compound should be prepared. These vials are processed according to the above procedure and analyzed by GC. The calibration curve consists of peak area ratio of a target compound to IS on the vertical axis and the concentration of a target compound on the horizontal axis. The peak area ratio obtained at the step v is applied to the calibration curve to obtain the concentration. Assessment and some comments on the method > Figure 1.2 shows gas chromatograms for the authentic diphenylmethane antihistaminics and for extracts of whole blood and urine in the presence and absence of 5 µg each of drugs per 1 mL obtained by the present method using a DB-1 capillary column. Many compounds ap- peared as sharp peaks. With an intermediately polar DB-17 capillary column, sharp peaks also appeared. By using both DB-1 and DB-17 columns, most compounds can be separated with sharp peaks; however phenyltoloxamine and orphenadrine (peaks 3 and 4) could not be sepa- rated with either column. With the DB-1 column, the peak of triprolidine (peak 9) overlapped an impurity peak of whole blood and urine extracts, and the peak of chlorpheniramine (peak 6) overlapped a small impurity peak of the whole blood extract. These problems could be over- come by using the DB-17 column. The recoveries of the drugs from human whole blood were not lower than 90 % except for meclizine; the latter shows 49.4 % recovery. The recoveries of the drugs from urine were also not lower than 90 % except benactyzine, piperilate and meclizine; those of the latter drugs were 64.6, 72.2 and 79.8 %, respectively. The detection limits for diphenylmethane antihistaminics using the capillary GC method are 0.2–0.5 µg/mL. To enhance sensitivity and specificity, GC/MS can be used; however, for most compounds, molecular or quasi-molecular peaks are missing in the positive EI mode [4]
  4. 318 ⊡ Figure 1.2 Diphenylmethane antihistaminics Capillary gas chromatograms for diphenylmethane antihistaminics extracted from whole blood and urine [4].
  5. HPLC analysis of diphenyhydramine in blood and urine 319 except for terolidine and triprolidine. For the latter compounds, relatively intense molecular ions appear to be used for sensitive detection. In the positive and negative CI modes, intense quasi-molecular ions appear for most drugs, which can be used for sensitive quantitation. HPLC analysis of diphenyhydramine in blood and urine [7] Diphenhydramine is one of the most popular drugs in this group, and its poisoning cases are many. In this section, one of the most common method by HPLC for diphenyldramine is described. Reagents and their preparation • Diphenhydramine hydrochloride and imipramine hydrochloride can be obtained from Sigma. • IS: imipramine hydrochloride is dissolved in distilled water to prepare 0.5 µg/mL solu- tion. • Extraction solutions: hexane/isopropanol (98:2, v/v), saturated potassium carbonate aque- ous solution and 0.5 % (v/v) phosphoric acid solution. HPLC conditions An HPLC system includes a usual conveying pump, an injector and a UV detector. Column: reversed phase ODS-1 Spherisorb (15 cm × 0.46 cm i. d., particle diameter 5 µm); mobile phase: acetonitrile/distilled water/1 M sodium dihydrogenphosphate solution (11:7:2, v/v); its flow rate: 1.8 mL/min: detection wavelength: 205 nm. Procedure i. To 1 mL of serum or urine, 100 µL of IS solution and 200 µL of saturated potassium car- bonate solution are added and extracted with hexane/isopropanol (98:2, v/v) by shaking. ii. To the organic phase, 100 µL of phosphoric acid solution for back-extraction of the com- pounds. An aliquot of the aqueous phase is injected into HPLC. Assessment of the method The retention times of diphenyhydramine and IS were 4.6 and 6.4 min, respectively. Linearity could be obtained in the range of 1–100 ng/mL; the detection limit was reported to be 1 ng/mL.
  6. 320 Diphenylmethane antihistaminics HPLC analysis of chlorpheniramine and its metabolites in blood and urine [8] Chlorpheniramine is one of the most popular antihistaminics, and has been being used for over 50 years. In this section, HPLC analysis of chlorpheniramine and its metabolites didemethyl- chlorpheniramine and demethylchlorpheniramine is described. Reagents and their preparation • Chlorpheniramine maleate and brompheniramine maleate are obtainable from Sigma. • IS: brompheniramine maleate is dissolved in distilled water to prepare 1 µg/mL solution. • Solutions to be used for extraction: 5 % KOH and 0.5 % phosphoric acid solutions. HPLC conditions An HPLC system to be used includes a usual conveying pump, an injector and a UV detector. Column: a reversed phase C18 column (30 cm × 0.39 cm i. d., particle diameter 5 µm); mobile phase: acetonitrile/75 mM phosphate buffer solution (pH 2.5) (25:75, v/v); its flow rate: 2 mL/ min; detection wavelength: 254 nm. Procedure i. To 1 mL of serum or urine, 100 µL of IS solution and 250 µL of 5 % KOH solution were added and extracted with 5 mL ethyl ether. ii. The target compounds are back-extracted from the organic phase by adding 0.5 mL of 0.5 % phosphoric acid solution. A 250-µL aliquot of 5 % KOH solution is added to the aqueous phase and again extracted with 5 mL ethyl ether. The organic layer is evaporated to dryness. iii. The residue is dissolved in 100 µL of the mobile phase, and an aliquot of it is injected into HPLC. Assessment of the method The retention times of didemethylchlorpheniramine, demethylchlorpheniramine, chlorphe- niramine and IS under the conditions were 2.7, 3.2, 4.3 and 5.0 min. Good linearity was found in the range of 0–30 ng/mL; the detection limit was reported to be 1 ng/mL. HPLC analysis of hydroxyzine in blood [9] Hydroxyzine has a similar structure to those of diphenylmethane antihistaminics, but is being widely used as an anxiolytic drug.
  7. Poisoning cases, and toxic and fatal concentrations 321 Reagents and preparation • Hydroxyzine dihydrochloride and triprolidine hydrochloride can be obtained from Sigma. • IS: triprolidine is dissolved in distilled water to prepare 1 µg/mL solution. • Solutions to be used for extraction: 10 % KOH and 1 % phosphoric acid aqueous solu- tions. HPLC conditions An HPLC system includes a usual conveying pump, an injector and a UV detector. Column: a reversed phase CN radial compression column (Waters, particle diameter 4 µm); mobile phase: acetonitrile/75 mM phosphate buffer solution (pH 3.0, containing 20 mM dibutylami- nef and 50 ng/mL triprolidine) (27:73, v/v); its flow rate: 1 mL/min; detection wavelength: 229 nm. Procedure i. To 1 mL serum, 100 µL of IS solution and 0.25 mL of 10 % KOH solution are added and extracted with 5 mL of diethyl ether. ii. The target compound and IS are back-extracted from the organic phase into an aqueous phase by adding 100 µL of 1 % phosphoric acid solution; an aliquot of the aqueous phase is injected into HPLC. Assessment of the method Under the conditions, the peaks of IS and hydroxyzine appeared at 3.6 and 6.9 min, respec- tively. Good linearity was observed in the range of 0–100 ng/mL; the detection limit was re- ported to be 3 ng/mL. In this method, triprolidine is used as IS; therefore, triprolidine can be measured by this method using hydroxyzine as IS conversely. Poisoning cases, and toxic and fatal concentrations The drugs reported to have caused deaths are diphenhydramine, dimenhydrinate and hydroxy- zine. The estimated fatal doses of diphenhydramine are 20–40 mg/kg; toxic symptoms usual appear after ingesting 3–5 times the therapeutic dose [14]. Plasma diphenhydramine concen- trations are: therapeutic, 0.1–1 µg/mL; toxic, not lower than 1 µg/mL [15]; fatal, not lower than 5 µg/mL [15–17]. Dimenhydrinate is a multi-component drug consisting of diphenhydramine (53–55 %) and 8-chlorotheophylline (44–47 %), and also sometimes very toxic at high doses. There are fatal cases in which 20–40 mg/kg of dimenhydrinate is ingested by adults and not more than 500 mg ingested by infants. In a fatal case of a victim, who had ingested 5 g dimenhydrinate, the concentration of diphenhydramine in urine was 10.8 µg/mL. It was reported that toxic
  8. 322 Diphenylmethane antihistaminics symptoms appeared for subjects whose urinary concentrations of diphenhydramine were not lower than 100 ng/mL [18]. Another fatal case with dimenhydrinate showing 4.8 ng/mL of blood diphenhydramine was reported [19]. For hydroxyzine, fatal cases were reported with its blood concentrations at 1.1 [20] and 39 µg/mL [21]; a poisoned but survived case was reported with its blood concentration as high as 103 µg/mL [22]. Usually, blood hydroxyzine concentrations not lower than 0.1 µg/mL cause poisoning symptoms [23, 24]. Orphenadrine (Disipal®) is being used as an antiparkinsonian drug and shows a weak antihistaminic action; since its structure is very similar to that of diphenhydramine, it is fre- quently used as IS for analysis of diphenylmethane antihistaminics. The fatal orphenadrine poisoning cases are many; its toxic blood concentrations are not lower than 2 µg/mL [25] and fatal ones not lower than 4–8 µg/mL [25, 26]. A fatal case involving chlorpheniramine was reported [27]. However, most of the poisoned patients survived; their blood concentrations of chlorpheniramine were 20–30 µg/mL [28]. Notes a) Any columns made of non-polar 100 % dimethylsilicone and intermediately polar 50 % phenylsilicone/50 % dimethylsilicone stationary phases can be used, regardless of their manufacturers. b) Any GC instrument for a capillary column can be used. c) The quality of the Sep-Pak C18 cartridges (classic type) being sold currently seems inferior to that of the same ones, which had been sold about 10 years ago. The previous ones could be reused after passing urine and plasma specimens, but new ones cannot be reused. With use of the Sep-Pak C18 cartridges, some impurity peaks due to the cartridges themselves may appear and interfere with the GC analysis according to a lot of the cartridges. In such a case, the conventional liquid-liquid extraction can be made in place of the solid-phase extraction. Briefly, after adding IS to a specimen, the solution is made alkaline by adding KOH or NaOH solution, followed by extraction with an organic solvent (diethyl ether or dichloromethane) [1]; the organic phase is back-extracted with acidic solution (phosphoric acid or hydrochloric acid) [5]. The aqueous extract is again made alkaline, followed by ex- traction with an organic solvent; the latter is condensed and subjected to GC analysis [2]. According to a specimen, the first organic extract can be directly used for GC analysis without the back-extraction. When an organic extract is evaporated to dryness, the residue is dissolved in a small amount of an organic solvent for GC analysis, or dissolved in a small amount of a mobile phase for HPLC analysis. d) As IS, one of other diphenylmethane antihistaminic, which shows a retention time close to that of a target drug, is selected; 5 µg of IS is added to 1 mL of whole blood or urine before extraction procedure. e) For a whole blood, a total volume of the specimen solution to be poured into the cartridge is 15 mL; 1 mL of a blood specimen is placed in a 50-mL volume beaker, followed by the addition of IS, 9 mL distilled water and 5 mL NaHCO3 solution and mixed well. Using a 10-mL volume glass syringe, 7.5 mL of the solution is drawn into it and poured into the cartridge slowly; this procedure is repeated to apply all of the solution onto the cartridge. f) It is used for preventing hydroxyzine from its adsorption to the HPLC column.
  9. Poisoning cases, and toxic and fatal concentrations 323 References 1) Yoo SD, Axelson JE (1986) Determination of diphenhydramine in biological fluids by capillary gas chromatogra- phy using nitrogen-phosphorus detection. Application to placental transfer studies in pregnant sheep. J Chro- matogr 378:385–393 2) Blyden GT, Greenblatt DJ, Scavone JM et al. (1986) Pharmacokinetics of diphenhydramine and demethylated metabolite following intravenous and oral administration. J Clin Pharmacol 26:529–533 3) Hattori H, Yamamoto S, Iwata M et al. (1992) Determination of diphenylmethane antihistaminic drugs and their analogues in body fluids by gas chromatography with surface ionization detection. J Chromatogr 581:213–218 4) Seno H, Hattori H, Kumazawa T et al. (1993) Positive- and negative-ion mass spectrometry of diphenylmethane antihistaminics and their analogues and rapid clean-up of them from biological samples. Forensic Sci Int 62:187–208 5) Simons K, Singh M, Gillespie CA et al. (1996) An investigation of the H1-receptor antagonist triprolidine : phar- macokinetics and antihistaminic effects. J Allergy Clin Immunol 77:326–330 6) Nishikawa M, Seno H, Ishii A et al. (1997) Simple analysis of diphenylmethane antihistaminics and their ana- logues in bodily fluids by headspace solid-phase microextraction-capillary gas chromatography. J Chromatogr Sci 35:275–279 7) Selinger K, Prevost J, Hill HM (1990) High-performance liquid chromatography method for the determination of diphenhydramine in human plasma. J Chromatogr 526:597–602 8) Simons KJ, Simons FER, Luciuk GH et al. (1984) Urinary excretion of chlorpheniramine and its metabolites in children. J Pharm Sci 73:595–599 9) Simons FER, Simons KJ, Frith EM (1984) The pharmacokinetics and antihistaminic of the H1 receptor antagonist hydroxyzine. J Allergy Clin Immunol 73:69–75 10) Simons KJ, Watson WTA, Chen XY et al. (1989) Pharmacokinetic and pharmacodynamic studies on the H1-re- ceptor antagonist hydroxyzine in the elderly. Clin Pharmacol Ther 45:9–14 11) Matsuda M, Mizuki Y, Terauchi Y (2001) Simultaneous determination of the histamine H1-receptor antagonist ebastine and its metabolites, carebastine and hydroxyebastine, in human plasma using high-performance liquid chromatography. J Chromatogr B 757:173–179 and 765:205 (erratum) 12) Nishikawa M, Nakai A, Fushida H et al. (1993) Enantioselective pharmacokinetics of homo-chlorcyclizine. III. Simultaneous determination of (+)- and (–)-homochlorcyclizine in human urine by high-performance liquid chromatography. J Chromatogr 612:239–244 13) Sakurai E, Yamasaki S, Iizuka Y et al. (1992) The optical resolution of racemic chlorpheniramine and its stereose- lective pharmacokinetics in rat plasma. J Pharm Pharmacol 44:44–47 14) Sakamoto T (ed and translation) (1999) Poisoning Handbook. Medical Science International Publication, Tokyo, pp 62–64 (in Japanese) 15) Fucci N (1996) A case of lethal intoxication after ingestion of toquilone compositum. Am J Forensic Med Pathol 17:231–232 16) Hausmann E, Wewer H, Wellhöner HH et al. (1983) Lethal intoxication with diphenhydramine. Report of a case with analytical follow-up. Arch Toxicol 53:33–39 17) Karch SB (1998) Diphenhydramine toxicity: comparisons of postmortem findings in diphenhydramine-, cocaine-, and heroin-related deaths. Am J Forensic Med Pathol 19:143–147 18) Winn RE, McDonnell KP (1993) Fatality secondary to massive overdoses of dimenhydrinate. Ann Emerg Med 22:1481–1484 19) Farrell M, Heinrichs M, Tilelli JA (1991) Response of life threatening dimenhydrinate intoxication to sodium bicarbonate administration. J Toxicol Clin Toxicol 29:527–535 20) Spiehler VR, Fukumoto RI (1984) Another fatal case involving hydroxyzine. J Anal Toxicol 8:242–243 21) Johnson GR (1984) A fatal case involving hydroxyzine. J Anal Toxicol 6:69–70 22) Magera BE, Betlach CJ, Sweatt AP et al. (1981) Hydroxyzine intoxication in a 13-month-old child. Pediatrics 67:280–283 23) Koyama K, Kikuno T, Kagami H et al. (2000) Blood concentrations and symptoms in acute hydroxyzine poisoning cases. J Nippon Hosp Pharm Assoc 26:13–16 (in Japanese) 24) Uges DRA (1997) Blood level data. In: Brandenberger H, Maes RAA (eds) Analytical Toxicology for Clinical, Forensic and Pharmaceutical Chemists. Walter de Gruyter, Berlin, pp 707–718 25) VanHarreweghe I, Mertens K, Maes V et al. (1999) Orphenadrine poisoning in a child: clinical and analytical data. Intens Care Med 25:1134–1136
  10. 324 Diphenylmethane antihistaminics 26) DeMercurio D, Chiarotti M, Giusti GV (1979) Lethal orphenadrine intoxication: report of a case. Z Rechtsmed 82:349–353 27) Read D (1981) A fatal case involving chlorpheniramine. J Toxicol Clin Toxicol 18:941–943 28) Winek CL (1977) Injury by chemical agents. In: Tedeschi CG, Eckert WG, Tedeschi LG (eds) Forensic Medicine, Vol. III. Saunders, Philadelphia, pp 1568–1587

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