This report reviews the clinical use, metabolism and toxicity of theophylline (Section 1). Current chromatographic and immunoassay methods for theophylline measurement are discussed and practical methods using high-performance liquid chromatography are described (Section 2). Results from the UK National scheme for theophylline quality control and from an experiment to investigate the degree of interference by 1,7-dimethylxanthine in routine assays for theophylline are discussed in Section 3.
References
1.
OuC-N. Efficacy of caffeine in the treatment of neonatal apnea. Am Assoc Clin Chem1985; 6: 1–5.
2.
JacksonRHMcHenryJLMorelandFBClinical evaluation of elixophyllin with correlaion of pulmonary function studies and theophyline serum levels in acute and chronic asthmatic patients. Dis Chest1964; 45: 75–8.
3.
MitenkoPOgilvieRI. Rational intravenous doses of theophylline. New Engl J Med1973; 289: 600–3.
4.
HendelesLWeinbergerM. Theophylline: ‘a state of the art review’. Pharmacotherapy1983; 3: 2–44.
5.
RussoME. Management of theophylline intoxication with charcoal haemoperfusion. N Engl J Med1979; 300: 24–6.
6.
Anon. Self-poisoning with theophylline. Lancet1985; i: 146–7.
7.
Dan-ShyaDTang-LiuDReigelmanS. The metabolism of theophylline to caffeine in adults. Res Commun Chem Path Pharmacol1981; 34: 371–80.
8.
DaviesHBettyDLeakeyTAre theophylline levels enough? In: New perspectives in Theophylline therapy Number 78. (Turner-WarwickMLevyJ, eds). International Congress and Symposium series. London: Royal Society of Medicine, 1984.
9.
PerssonCGAnderssonKE. Respiratory and cardiovascular effects of 3-mcthylxanthinc, a metabolite of theophylline. Acta Pharmacol Toxicol1977; 49: 529–36.
10.
CaldwellJLancasterRMonksTJSmithRL. The influence of dietary methylxanthines on the metabolism and pharmacokinetics of intravenously administered theophylline. Br J Clin Pharmacol1979; 4: 637–8.
11.
ArandaJVSitarDSParsonsWDPharmacokinetic aspects of theophylline in premature newborns. New Engl J Med1976; 295: 413–6.
12.
PiafskyKMStarDSRagnoREOgilvieRI. Theophylline disposition in patients with hepatic cirrhosis. New Engl J Med1977; 296: 1495–7.
13.
MucklowJC. The use of saliva in therapeutic drug monitoring. Therap Drug Monit1982; 4: 229–47.
14.
RylanceGWBeswickDTCullenRERobertsDGV. Re-evaluation of saliva for monitoring theophylline concentrations. Arch Dis Child1985; 60: 66–9.
15.
SomaniSMKhannaNNBadaHS. Caffeine and theophylline serum/CSF correlation in premature infants. J Pediatr1980; 96: 1091–3.
16.
PoisonJBKrzanowskiJJGoldmanALSzentivanyiA. Inhibition of human pulmonary phosphodiesterase activity by therapeutic levels of theophylline. Clin Exp Pharmacol Physiol1978; 5: 535–9.
17.
RuffinRENewhouseMT. Dipyramidole—is it a bronchodilator?Eur J Resp Dis1981; 62: 123–126.
18.
BrissonGRMalaisse-LagaeFMalaisseWJ. The stimulus-secretion coupling of glucose induced insulin release. VII. A proposed site of action of adenosine 3′5-cyclic monophosphate. J Clin Invest1972; 51: 232–41.
19.
HorrobinDFMankuMSFranksDJ. Hamet P. Methylxanthine phosphodiesterase inhibitors behave as prostaglandin antagonists in a perused rat mesenteric artery preparation. Prostalandins1977; 13: 33–40.
20.
KolbeckRCSpierWACarrierGOBransomeED. Apparent irrelevance of cyclic nucleotides to the relaxation of tracheal smooth muscle induced by theophylline. Lung1979; 156: 173–83.
21.
AllyAINakatsuK. Adenosine inhibition of isolated rabbit ileum and antagonism by theohylline. J Pharmacol Exp Ther1976; 199: 208–215.
22.
MarquandtDLParkerCWSullivanTJ. Poteniation of mast cell mediator release by adenosine. J Immunol1978; 120: 871–8.
23.
FredholmBBSydomA. Are the anti-allergic actions of theophylline due to antagonism at the adenosine receptor?Agents Actions1980; 10: 145–7.
24.
WarrenJBThomsonACochraneGM. Theophylline. In: Therapeutic Drug Monitoring.WiddopB, ed. No. 3 in series Contemporary Issues in Clinical Biochemistry. Churchill-Livingstone, 1985; 332–47.
25.
ArkinstallWWAtkinsMEWhiteKWStewartJH. A comparative trial of 8 hourly and 12 hourly dosing with sustained release aminophylline in asthmatic children. In: New Perspectives in Theophylline therapy: Number 78. Turner-WarwickMLevyJ, eds. London: The Royal Society of Medicine International Congress and Symposium Series, 1984; 39–47.
26.
DockhornRJGreenAWGreenE. Assessing the efficacy and safety of Q.D. theophylline therapy: a multicentre study. Annals Allergy1985; 55: 658–64.
27.
BurtonMEVaskoMRBraterDC. Comparion of drug dosing methods. Clin Pharmacokinetics1985; 10: 1–37.
28.
GiacoiaGJuskoWJMenkeJKoupJR. Theophylline pharmacokinetics in premature infants with apnea. JPediatr1976; 89: 829–829.
29.
NassifEGWeinbergerMGuiangSFJimenezD.Theophylline disposition in infancy. Preented to the American Academy of Pediatrics Annual Meeting. San Francisco, 1979.
30.
RosenJPDanishMRagniMCTheophyline pharmacokinetics in the young infant. Pediatrics1979; 64: 248–51.
31.
SimonsFERSimonsKJ. Pharmacokinetics of theophylline in infancy. J Clin Pharmacol1978; 18: 472–6.
32.
LoughnanPMSitarDSOgilvieRIPharmacokinetic analysis of the disposition of intravenous theophylline in younger children. J Pediatr1976; 88: 874–9.
33.
GinchanskyEWeinbergerM. Relationship of theophylline clearance to oral dosage in children with chronic asthma. J Pediatr1977; 91: 655–60.
34.
EllisEFKoysookoRLevyG. Pharmacokinetics of theophylline in children with asthma. Pediatrics1976; 58: 542–7.
35.
HendelesLWeinbergerMBighleyL. Disposiion of theophylline following a single intravenous aminophylline infusion. Am Rev Resp Dis1978; 118: 97–103.
36.
JuskoWJSchentagJJClarkJHEnhanced biotransformation of theophylline in marijuana and tobacco smokers. Clin Pharmacol Ther1978; 74: 406–10.
37.
PowellJRThiercelinJVozehSThe influence of cigarette smoking and sex on theophylline disposition. Am Rev Resp Dis1977; 116: 17–23.
38.
Nielsen-KudskFMagnussenIJakobsenP. Pharmacokinetics of theophylline in ten elderly patients. Acta Pharmacol Toxicol1978; 42: 226–34.
VicunaNMcNayJLLuddenTMSchwemerH. Impaired theophylline clearance in patients with cor pulmonale. Br J Clin Pharmacol1979; 7: 33–7.
41.
MangioneAImhoffTELeeRVPharmacokinetics of theophylline in hepatic disease. Chest1978; 73: 616–22.
42.
JenneJNagasawaHMcHughRDecreased theophylline half-life in cigarette smokers. Life Sci1975; 17: 195–8.
43.
WeinbergerMHudgelDSpectorSChidseyC. Inhibition of theophylline clearance by troleandomycin. J Allergy Clin Immunol1977; 59: 228–31.
44.
PriceRAWingDSWeinbergerMMEffect of erythromycin on theophylline kinetics. J Allergy Clin Immunol1981; 68: 427–31.
45.
LandayRAGonzalezMATaylorJC. Effect of phenobarbital on theophylline disposition. J Allergy Clin Immunol1978; 62: 27–9.
46.
KappasAAndersenKEConneyAHAlvaresAP. Influence of dietary protein and carboydrate on theophylline metabolism in man. Clin Pharmacol Ther1976; 20: 643–53.
47.
KappasAAlvaresAPAndersenKEEffect of charcoal-broiled beef on antipyrene and theophylline metabolism. Clin Pharmacol Ther1978; 23: 445–50.
48.
SchackJAWaxierSH. An ultraviolet spectrophotometric method for the determination of theophylline and theobromine in blood and tissues. J Pharmacol Exp Ther1949; 97: 283.
49.
JatlowP. Ultraviolet spectrophotometry of theophylline in plasma in the presence of barbiturates. Clin Chem1975; 21: 1518–20.
50.
VinetBZizianL. Enzymic assay for serum theophylline. Clin Chem1979; 25: 1370–72.
51.
BockJLLamSKarmenA. Therapeutic drug monitoring using high-speed liquid chromatography and rapid sample preparation: an assay for serum theophylline. J Chromatogr1984; 308: 354–8.
52.
MuirKTKunitaniMRiegelmanS. Improved high-performance liquid chromatographic assay for theophylline in plasma and saliva in the presence of caffeine and its metabolites and comparisons with three other assays. J Chromatogr1982; 231: 73–82.
53.
FranconiLCHawkGLSandmannBJHaneyWG. Determination of theophylline in plasma ultrafiltrate by reversed phase high pressure liquid chromatography. Anal Chem1976; 48: 372–5.
54.
AlbaniMToselandPA. A simple rapid gas chromatographic method for the determination of theophylline in dried whole blood on filter paper cards. Neuropaediatrie1978; 9: 97–9.
55.
CoombesEJGamlenTRBatstoneGFHolgateST. The validation of a fluoroimmunoassay for the determination of theophylline concentration in dried blood spots suitable for domiciliary therapeutic drug monitoring. Clin Chim Acta1984; 136: 187–95.
56.
SnyderLRVan der WalSj. The precision of assays based on high performance liquid chromatography with prior solvent extraction of the sample. Anal Chem1981; 53: 877–84.
57.
Van der WalSjSnyderLR. Precision of high-performance liquid chromatographic assays with sample pre-treatment. Error analysis for the Technicon FAST-LC system. Clin Chem1981; 27: 1233–40.
58.
StarkeyBJMouldFP. Evaluation of a rapid high-performance liquid chromatographic method for plasma theophylline analysis and its use in therapeutic drug monitoring. Therap Drug Monit1984; 6: 322–7.
59.
ZyssetTWahllanderAPreisigR. Evaluation of caffeine plasma levels by an automated enzyme immunoassay (EMIT) in comparison with a high performance liquid chromatographic method. Therap Drug Monit1984; 6: 348–54.
60.
Van AerdePhMoermanEVan SeerenRBraeckmanP. Determination of plasma theophylline by straight phase high performance liquid chromatography: elimination of interfering caffeine metabolites. J Chromatogr1981; 222: 467–74.
61.
NaishPJCookeMChambersRE. Rapid assay for theophylline in clinical samples by reversed phase high performance liquid chromatography. J Chromatogr1979; 163: 363–72.
62.
SchierGMGanIET. Measurement of plasma theophylline by gas-liquid chromatography on the stationary phase SP-2510. J Chromatogr1981; 255: 208–12.
63.
JohnsonGFDechtairukWASolomonHM. Gas chromatographic determination of theophylline in human serum and saliva. Clin Chem1975; 21: 144–7.
64.
PerrierDLearD. Gas chromatographic quantitation of theophylline in small volumes of plasma. Clin Chem1976; 22: 898–900.
65.
BaileyDGDavidHLJohnsonGE. Improved theophylline serum analysis by an appropriate internal standard for gas chromatography. J Chromatogr1976; 121: 263–8.
66.
FlobergSLindstromBLonnerholmG. Simultaneous determination of theophylline and caffeine after extractive alkylation in small volumes of plasma by gas chromatography-mass spectrometry. J Chromatogr1980; 221: 166–9.
67.
KabraPMMartonLJ. Liquid chromatographic analysis for serum theophylline in less than 70 seconds. Clin Chem1982; 28: 687–9.
68.
GuptaRJEngFStefanecM. Estimation of theophylline in plasma by thin-layer chromatography. Clin Biochem1978; 11: 42–5.
69.
ChrzanowskiFANiebergallPJNikellyJGGas chromatographic analysis of theophylline in human serum. Biochem Med1974; 11: 26–31.
70.
SheehanMHaythornP. Rapid gas chromatographic determination of underivatized theophylline in whole blood. J Chromatogr1976; 117: 393–8.
71.
SchwertnerHA. Analysis of underivatized theophylline by gas chromatography on a silicone stationary phase, SP-2510-DA. Clin Chem1979; 25: 212–14.
72.
VinetBZizianL. Improved determination of serum theophylline by gas chromatography with use of a nitrogen-phosphorus detector. Clin Chem1979; 25: 156–8.
73.
SchierGMGanIET. Micro-estimation of plasma theophylline by gas-liquid chromatography with on-column butylation and nitrogen specific detection. J Chromatogr1980; 182: 232–6.
74.
BerthouFDreanaYRicheCDetermination de la theophylline plasmatique due nouveaune par chromatographic en phase gazeuse a haute resolution et detection specifique. Ann Biol Clin (Paris)1978; 36: 497–507.
75.
SunSR. Rapid determination of theophylline in serum by electron capture GC. J Pharm Sci1979; 68: 443–5.
76.
WilsonJFMarshallRWWilliamsJRichensA. Accuracy and precision of gas-liquid chromatographic, high-pressure liquid chromatographic, and enzyme immunoassay techniques for the measurement of theophylline concentrations in serum. Comparison based on external quality assurance measurements. Ther Drug Monit1984; 6: 243–50.
77.
Wesley-HadzijaBMattocksAM. Specific thin-layer chromatographic method for the determination of theophylline in plasma in the presence of some other drugs. J Chromatogr1975; 115: 501–5.
78.
RiechertM. Micro-method for the determination of caffeine and theophylline allowing direct application of biological fluids to thin-layer chromatography plates. J Chromatogr1978; 146: 175–80.
79.
HeilweilETouchstoneJC. Theophylline analysis by direct application of serum to thin layer chromatograms. J Chromatogr Sci1981; 19: 595–7.
80.
FarrishHHWarginWA. Separation and quantitation of theophylline and paraxanthine by reversed-phase liquid chromatography. Clin Chem1980; 26: 524–5.
81.
MiksicJRHodesB. Eliminating 1,7-dimethylxanthine interference from reversed phase liquid-chromatographic analysis for theophylline. Clin Chem1979; 25: 1866–7.
82.
JonkmanJHGDe ZeeuwRASchoenmakerR. Interference in the proposed selected method for determination of theophylline by liquid chromatography. Clin Chem1982; 28: 1987–8.
83.
LewisECJohnsonDC. Evaluation of a glassy carbon electrode for emperometric detection of selected methylxanthines in serum after their separation by reversed-phase chromatography. Clin Chem1978; 24: 1711–9.
84.
WenkMEggsBFollathF. Simultaneous determination of diprophylline, proxphylline and theophylline in serum by reversed phase high-performance liquid chromatography. J Chromatogr1983; 276: 341–8.
85.
HartleyRCookmanJRSmithIJ. Simultaneous determination of caffeine and its N-demethylated metabolites in umbilical cord plasma using high-performance liquid chromatography. J Chromatogr1984; 306: 191–203.
86.
ScottNRChakrabortyJMarksV. Determination of caffeine, theophylline and theobromine in serum and saliva using high-performance liquid chromatography. Ann Clin Biochem1984; 21: 120–4.
87.
BroussardLA. Theophylline determination by high pressure liquid chromatography. Clin Chem1981; 27: 1931–3.
88.
BroussardLA. Interference in the proposed selected method for determination of theophylline by liquid chromatography. Clin Chem1982; 28: 1988.
89.
GannonRHLevyRM. Interference of third-generation cephalosporins with theophylline assay by high-performance liquid chromatography. Am J Hosp Pharm1984; 41: 1185–6.
90.
KellyRCPrenticeDEHearneGM. Cephalosporin antibiotics interfere with the analysis for theophylline by high performance liquid chromatography. Clin Chem1978; 24: 838–9.
91.
RobinsonCAJr.MitchellBVasiliadesJSiegelAL. Cephalosporin antibiotic interference with analysis for theophylline by high-performance liquid chromatography. Clin Chem1978; 24: 1847.
92.
LamGHuangS-MLeeM-GObviating interference with liquid chromatographic assay of theophylline. Clin Chem1979; 25: 1862–3.
93.
BowmanDBAravindMKKauffmanREMiceliJN. Sulfamethoxazole interferes with liquid-chromatographic analysis for theophylline in serum. Clin. Chem1980; 26: 1622.
94.
WeidnerNDietzlerDNLadensonJHA clinically applicable high pressure liquid chromatographic method for measurement of serum theophylline, with detailed evaluation of interferences. Am J Clin Pathol1980; 73: 79–86.
95.
RobinsonCAJrDobbsJ. Acetazolamide interference with theophylline analysis by high-performance liquid chromatography. Clin Chem1978; 24: 2208–9.
96.
OpheimKEAinardiVRaisysVA. Increase in apparent theophylline concentration in the serum of two uraemic patients as measured by some immunoassay methods (caused by 1,3 dimethyl uric acid?). Clin Chem1983; 29: 1698–9.
97.
VolcichRBSchierGMGanIE. Seralyser ARIS and Abbott TD. Theophylline II Assay Systems Compared. Clin Chem1985; 31: 1912.
98.
TurnbullJDMoshrigRGereJAKochalkaJ. Caffeine measured in serum from infants with the theophylline channel of the Abbott TD. Clin Chem1984; 30: 1721.
99.
BreinerRMcCombR. Positive interference with immunoassay of theophylline in serum of uremics. Clin Chem1985; 31: 1575–6.
100.
WongSHYMarzonkN. Letter to the Editor. Clin Chem1985; 31: 1576–7.
101.
DodgeRH. Caffeine no longer measurable with the theophylline Channel of the TD. Clin Chem1985; 31: 496.
102.
VaughanLMWeinbergerMMMilawetzGMulticentre evaluation of disposable visual measuring device to assay theophylline from capillary blood samples. Lancet1986; i: 184–6.
103.
NeeseALSoykaLF. Development of a radioimmunoassay for theophylline. Clin Pharm Therap1977; 21: 633–41.
104.
HodgkinsonAJSidkiAMLandonJDirect determination of theophylline in serum by fluoroimmunoassay using highly specific antibodies. Ann Clin Biochem1985; 22: 519–25.
105.
CastroASteeleB. A fluorescent immunoassay for theophylline: description and comparison to enzyme immunoassay, liquid chromatography and radioimmunoassay. Clin Biochem1983; 16: 281–4.
106.
SheenAESlyMRHiteSComparison of serum theophylline concentrations measured by high pressure liquid chromatography and quantitative enzyme multiplied immunoassay technique. Annals Allergy1979; 42: 77–9.
107.
BoobisS. Interlaboratory variability in determination of serum theophylline concentrations—results of a quality control programme. Br J Clin Pharmacol1979; 7: 437P–438P.
108.
HealyMJR. Outliers in clinical chemistry quality control schemes. Clin Chem1979; 25: 675–7.
109.
Dan-ShyaDTang-LiuDWilliamsRLReigelmanS. Disposition of caffeine and its metabolites in man. J Pharmacol Exp Ther1973; 224: 180–5.
110.
OgilvieRI. Clinical pharmacokinetics of theophylline. Clin Pharmacol1978; 12: 267–93.
111.
MarksVKellyJF. Absorption of caffeine from tea, coffee and coca-cola. Lancet1973; i: 827.
112.
ChristensenHDWhitsettTL. Measurements of xanthines and their metabolites by means of high pressure liquid chromatography. In: Biological/Biomedical Application of Liquid Chromatography (HawkG L, ed). Chromatographic Science Scries Vol. 10. New York, Basel: Marcel Dekker, 1979; 507–37.