Summary
In the last 20 years, there has been considerable improvement in the determination of anticonvulsive drugs in body fluids. Gas-liquid chromatography, high-performance liquid chromatography and immunological methods (radio-, enzyme-, fluoro-, and nephelo-immunoassays) have progressively supplanted spectrophotometry and thin-layer chromatography. As the number of publications shows, these methods have included a great variety of procedures. At present, gas-liquid chromatography and enzyme-immunoassays are routinely performed, awaiting a wider spread of liquid chromatography and other immunological techniques.
This paper is a comprehensive review of the analytical literature on the determination of phenobarbitone, primidone, phenytoin, carbamazepine, valproic acid, ethosuximide, clonazepam, and some of their metabolites in physiological fluids. Gas-liquid chromatographic methods are more particularly reviewed.
In order to facilitate the choice between these procedures, a critical selection of the techniques is given and recommendations are made. Emphasis is laid on technical problems encountered with the assays, as well as the need for a rigorous analytical assessment and internal and external quality controls. This review is completed by considerations on the determination of the free drug fraction and on sample collection and storage.
Zusammenfassung
In den letzten zwanzig Jahren wurde die Bestimmung von Antiepileptica in Körperflüssigkeiten erheblich weiterentwickelt. Die Gas-Flüssigkeitschromatographie, die sehr leistungsfähige Flüssigkeitschromatographie und immunologische Methoden (Röntgen-, Enzym-, Fluor- und Nephelo-Immunprüfungen) haben allmählich die Spektrophotometrie und die Dünnschichtchromatographie verdrängt. Wie die Zahl der Veröffentlichungen zeigt, wurden diese Methoden in eine Vielfalt von Verfahren aufgeteilt. Heutzutage werden Gas-Flüssigkeitschromatographie und Enzym-Immunoprüfungen routinemäßig durchgeführt, in Erwartung einer weiteren Verbreitung der Flüssigkeitschromatographie und sonstiger immunologietechnischer Methoden.
Die vorliegende Abhandlung stellt eine Übersicht des analytischen Schrifttums über die Bestimmung von Phenobarbital, Primidone, Phenytoin, Carbamazepin, Valproicsäure, Ethosuximid, Clonazepam und einigen ihrer Metaboliten in Körperflüssigkeiten dar. Gas-Flüssigkeitschromatographiemethoden werden besonders eingehend dargelegt.
Um die Wahl zwischen diesen Methoden zu erleichtern, wird eine kritische Auswahl der technischen Methoden und Empfehlungen beschrieben. Technische Probleme bei den Untersuchungen sowie die Notwendigkeit einer genauen analytischen Technik und interner wie externer Qualitätskontrollen werden hervorgehoben. Vervollständigt wird diese Übersicht durch Überlegungen über die Bestimmung der freien Arzneimittel und über Entnahme und Aufbewahrung der Proben.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Adams RF, Schmidt GJ, Vandemark FL (1978) A micro liquid column chromatography procedure for twelve anticonvulsants and some of their metabolites. J Chromatogr 145:275–284
Ayers GJ, Goudie JH, Reed K, Burnett D (1977) Quality control in the simultaneous assay of anticonvulsants using an automated gas chromatographic system with a nitrogen detector. Clin Chim Acta 76:113–124
Aymard P, Boulu RG, Sarhan N (1978) Dosage du phenobarbital et de la phénytome: revue critique. Ann Biol Clin (Paris) 36:149–156
Bastiani R (1975) Performance evaluation of the EMIT diphenylhydantoin and phenobarbital assays. Clinical study no. 20 summary report. Syva Co., Palo Alto, California, USA
Booker HE, Darcey BA (1975) Enzymatic immunoassay vs. gas/liquid chromatography for determination of phenobarbital and diphenylhydantoin in serum. Clin Chem 21:1766–1768
Buchanan RA, Fernandez L, Kinkel AW (1969) Absorption and elimination of ethosuximide in children. J Clin Pharmacol 9:393–398
Buchthal F, Svensmark O (1960) Aspects of the phamacology of phenytoin and phenobarbital relevant to their dosage in the treatment of epilepsy. Epilepsia 1:373–384
Chang T, Glazko AJ (1968) Quantitative assay of 5,5-diphenylhydantoin (DPH) and 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH) in plasma and urine of human subjects. Clin Res 16:339
Cook CE (1978) Radioimmunoassay. In: Pippenger CE, Penry JK, Kutt H (eds) Antiepileptic drugs: quantitative analysis and interpretation. Raven Press, New York, pp 163–173
Danhof M, Breimer DD (1978) Therapeutic drug monitoring in saliva. Clin Pharmacokinet 3:39–57
de Silva JAF, Bekersky I (1974) Determination of clonazepam and flunitrazepam in blood by electron capture gas liquid chromatography. J Chromatogr 99:447–460
de Silva JAF, Puglisi CV, Munno N (1974) Determination of clonazepam and flunitrazepam in blood and urine by electron capture GLC. J Pharm Sci 63:520–527
Dhar AK, Kutt H (1981) Improved gas chromatographic procedure for the determination of clonazepam levels in plasma using a nitrogen-sensitive detector. J Chromatogr 222:203–211
Dijkhuis IC, De Jong HJ, Richens A, Pippenger CE, Leskinen EEA, Nyberg APW (1979) Joint international quality control programme on the determination of antiepileptic drugs. Pharm Weekblad [Sci] 114:151–184
Dijkhuis IC, Vervloet E (1974) Rapid determination of the antiepileptic drug di-n-propylacetic acid in serum. Pharm Weekblad [Sci] 109:1–4
Dolan JW, van der Wal S, Bannister SJ, Snyder LR (1980) On-line liquid chromatographic analysis for drugs in serum with the Technicon “Fast-LC” system: performance data for theophylline and for four commonly used anticonvulsants and their metabolites. Clin Chem 26:871–880
Dudley KH (1978) Internal standards in gas-liquid chromatographic determination of antiepileptic drugs. In: Pippenger CE, Penry JK, Kutt H (eds) Antiepileptic drugs: quantitative analysis and interpretation. Raven Press, New York, pp 19–34
Dykeman RW, Ecobichon DJ (1979) Simultaneous determination of phenytoin, phenobarbital and their p-hydroxylated metabolites in urine by reverse-phase high performance liquid chromatography. J Chromatogr 162:104–109
Eadie MJ, Tyrer JH (1980) Anticonvulsant therapy. Phamacological basis and practice. Churchill Livingstone, Edinburgh
Evans JE (1973) Simultaneous measurement of diphenylhydantoin and phenobarbital in serum by high performance liquid chromatography. Anal Chem 45:2428–2429
Friel P, Troupin AS (1975) Flash-heater ethylation of some antiepileptic drugs. Clin Chem 21:751–754
Garland WA, Min BH (1979) Determination of clonazepam in human plasma by gas chromatography-negative ion chemical ionization mass spectrometry. J Chromatogr 172:279–286
Garland WA, Powell ML (1981) Quantitative selected ion monitoring (QSIM) of drugs and/or drug metabolites in biological matrices. J Chromatogr Sci 19:392–434
Goldbaum LR (1952) Determination of barbiturates. UV spectrophotometric method with differentiation of several barbiturates. Anal Chem 24:1604–1607
Greeley RH (1974) New approach to derivatization and gas-chromatographic analysis of barbiturates. Clin Chem 20:192–194
Griffiths A, Hebdige S, Perucca E, Richens A (1980) Quality control in drug measurement. Ther Drug Monit 2:51–59
Hamilton HE, Wallace JE (1978) Ultraviolet spectrophotometric quantitation of phenytoin and phenobarbital. In: Pippenger CE, Penry JK, Kutt H (eds) Antiepileptic drugs: quantitative analysis and interpretation. Raven Press, New York, pp 175–183
Johannessen SI (1981) Antiepileptic drugs: pharmacokinetic and clinical aspects. Ther Drug Monit 3:17–37
Jolley ME, Stroupe SD, Schwenzer KS, Wang CJ, Lu-Steffes M, Hill HD, Popelka SR, Holen JT, Kelso DM (1981) Fluorescence polarization immunoassay. III. An automated system for therapeutic drug determination. Clin Chem 27:1575–1579
Kabra PM, Stafford BE, Marton LJ (1977) Simultaneous measurement of phenobarbital, phenytoin, primidone, ethosuximide and carbamazepine in serum by high pressure liquid chromatography. Clin Chem 23:1284–1288
Kelly RC, Valentour JC, Sunshine I (1977) Solvent suppression of the decomposition of phenobarbital during on-column methylation with trimethylanilinium hydroxyde. J Chromatogr 138:413–422
Kossa WC, MacGee J, Ramachandran S, Webber AJ (1979) Pyrolytic methylation/gas chromatography: a short review. J Chromatogr Sci 17:177–187
Kumps A (1980) Dosage du phénobarbital, de la phénytoine et de la primidone dans le sérum par chromatographie en phase gazeuse. Anal Lett [BIO] 13:909–919
Kumps A, Kumps-Grandjean B, Mardens Y (1981) Enzyme immunoassay and gas-liquid chromatography compared for determination of valproic acid in serum. Clin Chem 27:1788–1789
Kumps A, Mardens Y (1980) Improved gas-liquid chromatographic method for the simultaneous determination of phenobarbital, phenytoin, carbamazepine and primidone in biological fluids. J Chromatogr 182:116–120
Kumps A, Mardens Y (1980) Simplified simultaneous determination of valproic acid and ethosuximide in serum by gas-liquid chromatography. Clin Chem 26:1759
Kumps A, Mardens Y, Scharpé S (1980) Comparison between high-performance liquid chromatography, gas-liquid chromatography and enzyme immunoassay for the determination of antiepileptic drugs in serum. In: Johannessen SI, Morselli PL, Pippenger CE, Richens A, Schmidt D, Meinardi H (eds) Antiepileptic therapy: advances in drug monitoring. Raven Press, New York, pp 341–347
Kupferberg HJ (1970) Quantitative estimation of diphenylhydantoin, primidone and phenobarbital in plasma by gas-liquid chromatography. Clin Chim Acta 29:283–288
Kupferberg HJ (1978) Gas-liquid chromatographic quantitation of valproic acid. In: Pippenger CE, Penry JK, Kutt H (eds) Antiepileptic drugs: quantitative analysis and interpretation. Raven Press, New York, pp 147–151
Larking P (1980) Gas chromatographic determination of clonazepam. J Chromatogr 221:399–402
Legaz M, Raisys VA (1976) Correlation of the “Emit” antiepileptic drug assay with a gas liquid chromatographic method. Clin Biochem 9:35–38
MacGee J (1970) Rapid determination of diphenylhydantoin in blood plasma by gas-liquid chromatography. Anal Chem 42:421–422
MacGee J (1971) Rapid identification and quantitative determination of barbiturates and glutethimide in blood by gas-liquid chromatography. Clin Chem 17:587–591
Marks V (1981) Immunoassays for drugs. In: Richens A, Marks V (eds) Therapeutic drug monitoring. Churchill Livingstone, Edinburgh, pp 155–182
Mihaly GW, Phillips JA, Louis WJ, Vajda FJ (1977) Measurement of carbamazepine and its epoxide metabolite by high-performance liquid chromatography, and a comparison of assay techniques for the analysis of carbamazepine. Clin Chem 23:2283–2287
Millner SN, Taber CA (1979) Rapid gas-liquid chromatographic determination of carbamazepine for routine therapeutic monitoring. J Chromatogr 163:96–102
Morselli PL, Franco-Morselli R (1980) Clinical pharmacokinetics of antiepileptic drugs in adults. Pharmacol Ther 10:65–101
Naestoft J, Larsen NE (1974) Quantitative determination of clonazepam and its metabolites in human plasma by gas chromatography. J Chromatogr 93:113–127
Nishikawa T, Kubo H, Saito M (1979) Competitive nephelometric immunoassay method for antiepileptic drugs in patient blood. J Immunol Methods 29:85–89
Osiewicz R, Aggarwal V, Young RM, Sunshine I (1974) The quantitative analysis of phenobarbital with trimethylanilinium hydroxyde. J Chromatogr 88:157–164
Parry GJG, Ferry DG (1976) Rapid gas chromatographic method for the determination of clonazepam in serum and cerebrospinal fluid. J Chromatogr 128:166–168
Perchalski RJ, Scott KN, Wilder BJ, Hammer RH (1973) Rapid, simultaneous GLC determination of phenobarbital, primidone, and diphenylhydantoin. J Pharm Sci 62:1735–1736
Pippenger CE (1979) Therapeutic drug monitoring: an overview. Ther Drug Monit 1:3–9
Pippenger CE, Gillen HW (1969) Gas chromatographic analysis for anticonvulsant drugs in biological fluids. Clin Chem 15:582–590
Pippenger CE, Paris-Kutt H, Penry JK, Daly D (1977) Proficiency testing in determinations of antiepileptic drugs. J Anal Toxicol 1:118–122
Pippenger CE, Penry JK, Kutt H (1978) Antiepileptic drugs: quantitative analysis and interpretation. Raven Press, New York
Pippenger CE, Penry JK, White BG, Daly D, Buddington R (1976) Interlaboratory variability in determination of plasma antiepileptic drug concentrations. Arch Neurol 33:351–355
Rambeck B, Meijer JWA (1979) Comprehensive method for the determination of antiepileptic drugs using a novel extraction technique and a fully automated gas chromatograph. Arzneimittelforsch 29:99–103
Rambeck B, Meijer JWA (1980) Gas chromatographic methods for the determination of antiepileptic drugs: a systematic review. Ther Drug Monit 2:385–396
Rambeck B, Riedmann M, Meijer JWA (1981) Systematic method of development in liquid chromatography applied to the determination of antiepileptic drugs. Ther Drug Monit 3:377–395
Reynolds EH (1980) Serum levels of anticonvulsant drugs: interpretation and clinical value. Pharmacol Ther 8:217–235
Richens A, Marks V (1981) Therapeutic drug monitoring. Churchill Livingstone, Edinburgh
Riedmann M, Rambeck B, Meijer JWA (1981) Quantitative simultaneous determination of eight common antiepileptic drugs and metabolites by liquid chromatography. Ther Drug Monit 3:397–413
Roger J-C, Rodgers G, Jr, Soo A (1973) Simultaneous determination of carbamazepine (“Tegretol”) and other anticonvulsants in human plasma by gas-liquid chromatography. Clin Chem 19:590–592
Rovei V, Sanjuan M (1980) Simple and specific high performance liquid chromatographic method for the routine monitoring of clonazepam in plasma. Ther Drug Monit 2:283–287
Schwertner HA, Hamilton HE, Wallace JE (1978) Analysis for carbamazepine in serum by electron-capture gas chromatography. Clin Chem 24:895–899
Sichler DW, Pippenger CE (1978) Phenobarbital, carbamazepine, primidone, and phenytoin: simultaneous determination with on-column methylation (TMPAH). In: Pippenger CE, Penry JK, Kutt H (eds) Antiepileptic drugs: quantitative analysis and interpretation. Raven Press, New York, pp 335–338
Solow EB, Kenfield CP (1977) A micromethod for the determination of clonazepam in serum by electron-capture gas-liquid chromatography. J Anal Toxicol 1:155–157
Solow EB, Jennison TA, Lodmell JD, Frings CS (1982) Determination of phenobarbital and phenytoin by gas-liquid chromatography with on-column methylation. Clin Chem 28:216–218
St. Onge LM, Dolar E, Anglim MA, Least CJ, Jr (1979) Improved determination of phenobarbital, primidone, and phenytoin by use of a preparative instrument for extraction, followed by gas chromatography. Clin Chem 25:1373–1376
Svensmark O, Kristensen P (1963) Determination of diphenylhydantoin and phenobarbital in small amounts of serum. J Lab Clin Med 61:501–507
Szabo GK, Browne TR (1982) Improved isocratic liquid-chromatographic simultaneous measurement of phenytoin, phenobarbital, primidone, carbamazepine, ethosuximide, and N-desmethylmethsuximide in serum. Clin Chem 28:100–104
Thoma JJ, Ewald T, McCoy M (1978) Simultaneous analysis of underivatized phenobarbital, carbamazepine, primidone, and phenytoin by isothermal gas-liquid chromatography. J Anal Toxicol 2:219–225
Truscott RJW, Burke DG, Korth J, Halpern B, Summons R (1978) Simultaneous determination of diphenylhydantoin, mephobarbital, carbamazepine, phenobarbital and primidone in serum using direct chemical ionization mass spectrometry. Biomed Mass Spectrom 5:477–482
van der Kleijn E, Collste P, Norlander B, Agurell S, Sjöqvist F (1972) Gas chromatographic determination of ethosuximide and phensuximide in plasma and urine of man. J Pharm Pharmacol 25:324–327
Wad NT, Rosemund H (1978) Rapid quantitative method for the simultaneous determination of carbamazepine, carbamazepine-10,11-epoxide, diphenylhydantoin, mephenytoin, phenobarbital, and primidone in serum by thin-layer chromatography. Improvement in the buffer system. J Chromatogr 146:361–362
Westenberg HGM, de Zeeuw RA (1976) Rapid and sensitive liquid chromatographic determination of carbamazepine suitable for use in monitoring multiple-drug anticonvulsant therapy. J Chromatogr 118:217–224
Williams RC, Viola JL (1979) Application of an automated extractor/concentrator to the analysis of anticonvulsant drugs in blood serum by high-performance liquid chromatography. J Chromatogr 185:505–513
Wong RC, Burd JF, Carrico RJ, Buckler RT, Thoma J, Boguslaski RC (1979) Substrate-labeled fluorescent immunoassay for phenytoin in human plasma. Clin Chem 25:686–691
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kumps, A.H. Therapeutic drug monitoring: A comprehensive and critical review of analytical methods for anticonvulsive drugs. J Neurol 228, 1–16 (1982). https://doi.org/10.1007/BF00313405
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00313405