Determination

The determination of serum phenytoin levels has proven to be useful in seizure patients where steady state total blood levels usually serve as a guide to effective seizure control, and in determining insufficient or excessive doses, or noncompliance. In nonseizure disorders the correlation of blood levels with therapeutic effects varies. For example, in cardiac arrhythmias the effective blood level range has been reported to be similar to that used for seizure control. However, in thought, mood and behavior disorders, therapeutic effects are frequently observed at much lower blood levels. For patients with the disorders for which PHT is effective, routine blood levels are not necessary, especially when doses of 100-300 mg/day are being used and the desired therapeutic effect is being achieved.

Increasing attention is being devoted to the question of whether free, and not just total, PHT levels should be measured. See Refs.

2301. Bachmann, K., Voeller, K., Forney, B., Use of plasma unbound drug concentrations in adjusting phenytoin doses, Ther. Drug Monit., 6(2): 173-8, 1984.
2315. Bauer, L. A., Edwards, W. A., Dellinger, E. P., Raisys, V. A., Brennan, C., Importance of unbound phenytoin serum levels in head trauma patients, J. Trauma, 23: 1058-60, 1983.
2354. Braun, C. W., Goldstone, J. M., Increased clearance of phenytoin as the presenting feature of infectious mononucleosis, Ther. Drug. Monit., 2(4); 355-57, 1980.
2365. Bryson, S. M., Kelly, J. C., Kelman, A. W., Whiting, B., Therapeutic free phenytoin monitoring, Clin. Pharmacokinet., 9 (sup 1): 90, 1984.
2488. Feldman, R. C., Pippinger, C. E., Florence, M. L., The relation of anticonvulsant drug levels to complete seizure control, Epilepsia, 16(l): 203-4, 1975.
2514. Frisk-Holmberg, M., Hellstrom, L., Holmstrom, M., Dahlberg, E., Jakobsson, A. K., Utilization of blood drug level determinations for therapy monitoring, Lakartidningen, 77: 1316-7, 1980.
2661. Kilpatrick, C. J., Wanwimolruk, S., Wing, L. M., Plasma concentrations of unbound phenytoin in the management of epilepsy, Br. J. Clin. Pharmacol., 17(5): 539-46, 1984.
2679. Kupersmith, J., Monitoring of antiarrhythmic drug levels: values and pitfalls, Clinical Pharmacology of Cardiac Antiarrhythmic Agents: Classical and Current Concepts Reevaluated, Carfein, 0. B., Ed., N.Y. Acad. Sci., 432: 138-54, 1984.
2704. Leppik, I. E., Fisher, J., Kriel, R., Sawchuck, R., Altered phenytoin clearance during febrile illnesses, Neurology, 31(2): 158, 1981.
2706. Leppik, I. E., Ramani, V., Sawchuk, R. J., Cummit, R. J., Seizures and altered phenytoin metabolism in mononucleosis. Advances in Epileptology: The 10th Epilepsy International Symposium. Wada, J. A., Penry, J. K., Eds., Raven Press, New York, 506-7, 1980.
2713. Levy, R. H., Moreland, T. A., Rationale for monitoring free drug levels, Clin. Pharmacokinet., 9 (sup 1): 1-9, 1984.
2714. Levy, R. H., Schmidt, D., Utility of free level monitoring of antiepileptic drugs, Epilepsia, 26(3): 199-205, 1985.
2839. Oellerich, M., Muller Vahl, H., The EMIT free level (TM) ultrafiltration technique compared with equilibrium dialysis and ultracentrifugation to determine protein binding of phenytoin, Clin. Pharmacokin., 9 (Sup. 1) 61-70, 1984.
2860. Perucca, E., Crema, A., Therapeutic monitoring of serum antiepileptic drug levels, Epilepsy: An Update on Research and Therapy, Nistico, G., et al., eds., Alan R. Liss, Inc., New York, 267-83, 1983. 
2866. Peterson, C. M., McLean, S., Monitoring free plasma concentrations of phenytoin, Br. J. Clin. Pharmacol., 18(6): 971-2, 1984.
2908. Rimmer, E. M., Buss, D. C., Routledge, P. A., Richen, A., Should we routinely measure free plasma phenytoin concentration?, Br. J. Clin. Pharmacol., 17(l): 99-102, 1984.
3011. Theodore, W. H., Yu, L., Price, B., Yonekawa, W., Porter, R. J., Kapetanovic, I., Moore, H., Kupferberg, H., The clinical value of free phenytoin levels, Ann. Neurol., 18: 90-3, 1985.
3034. Turnbull, D. M., Rawlins, M. D., Weightrnan, D., Chadwick, D. W., “Therapeutic” serum concentration of phenytoin: the influence of seizure type, J. Neural. Neurosurg. Psychiatry, 47(3): 231-4, 1984.
3045. Van Hoeck, G. M., Comparison study between anticonvulsants assays and their free fractions in serous blood, saliva and capillary blood in man, J. Pharmacol., 15(l): 27-35, 1984.

New assays for the determination of PHT levels are continually being developed. These include gas chromatography and immunological techniques. Miniaturization has been achieved so that salivary samples or even capillary blood from a finger stick may be used (see Refs. 2286, 2299, 2313, 2426, 2580, 2663, 2840, 3038, 3045). A home assay has been introduced (see Refs. 2403, 2404). It is beyond the scope of this bibliography to review all these methods. The reader is referred to the following:

2286. Aman, M. C., Paxton, J. W., Werry, J. S., Fluctuations in steady-state phenytoin concentrations as measured in saliva in children, Pediatr. Pharmacol., 3: 87-94, 1983.
2299. Bachmann, K., Forney, R. B., Voeller, K., Monitoring phenytoin in salivary and plasma ultrafiltrates of pediatric patients, Ther, Drug Monit., 5(3): 325-9, 1983.
2313. Bartels, H., Cutber, E., Wallis, S., Monitoring therapy by analysis of drug concentration in saliva, Monatsschr. Kinderheilkd., 131(1): 13-16, 1983.
2426. Danhof, M., Breimer, D. D., Therapeutic drug monitoring in saliva, Handbook of Clinical Pharmacokinetics, Gibaldi, M., Prescott, L., Eds., New York, ADIS Health Science Press, 207-27, 1983. 
2580. Hassell, T., O’Donnell, J., Pearlman, J., Salivary phenytoin levels in institutionalized epileptics, J. Chronic Dis., 36(12): 899-9W, 1983.
2663. Knott, C., Reynolds, F., The place of saliva in anti-epileptic drug monitoring, Ther. Drug Monit., 6(l): 35-41, 1984.
2840. Ogura, C., Kunimoto, N., Kishirnoto, A., Takeshita, H., Mizukawa, R., Tsutsui, T., Hazama, H., Ryoke, K., Kurooka, S., Diphenylhydantoin concentrations in whole saliva, parotid saliva and plasma measured by enzyme immunoassay kit, Markit, Yonago Acta Med., 26(2-3): 55-64, 1983.
3038. Umstead, C. S., McKernan, T. M., Salivary phenytoin concentrations in geriatric patients, Epilepsy Abstracts, 15(9): 340, 1982.
3045. Van Hoeck, G. M., Comparison study between anticonvulsants assays and their free fractions in serous blood, saliva and capillary blood in man, J. Pharmacol., 15(l): 27-35, 1984.
2403. Coombes, E. J., Phenytoin assay on dried blood spots, Neurology, 34: 703, 1984.
2404. Coombes, E. J., Camlen, T. R., Batstone, G. F., Leigh, P. N., A phenytoin assay using dried blood spot samples suitable for domiciliary therapeutic drug monitoring, Ann. Clin. Biochem., 21(6): 519-22, 1984.
2277. Ahmad, S. N., Jailkhani, B. L., Jaffery, N. F., A rapid method for separation and estimation of free phenytoin in serum, Indian J. Exp. Biol., 22(11): 605-7, 1984.
2295. Apple, F. S., Walker, F. C., Dietzler, D. N., Serum creatinine concentration and the discrepancy between EMIT and GLC phenytoin levels, Clin. Chem., 28(7): 1589, 1982.
2303. Bailey, E., Farmer, P. B., Hoskins, J. A., Lamb, J. H., Peal, J. A., Determination of Plasma phenytoin by capillary gas chromatography with nitrogen-phosphorus detection and with selective ion monitoring, J. Chromatogr., 310(l): 199-203, 1984.
2346. Bock, J. L., Ben-Ezra, J., Rapid measurement of free anticonvulsant drugs by direct liquid chromatography of serum ultrafiltrates, Clin. Chem., 31(11): 1884-7, 1985.
2400. Cook, C. E., Christensen, H. D., Amerson, E. W., Kepler, J. A., Tallent, C. B., Taylor, C. F., Radioimmunoassay of anticonvulsant drugs: Phenytoin, phenobarbital, and primidone, Quantitative Analytic Studies in Epilepsy, Kellaway, P. and Petersen, I., Eds., Raven Press, New York, 39-58, 1976.
2403. Coombes, E. J., Phenytoin assay on dried blood spots, Neurology, 34: 703, 1984.
2404. Coombes, E. J., Camlen, T. R., Batstone, G. F., Leigh, P. N., A phenytoin assay using dried blood spot samples suitable for domiciliary therapeutic drug monitoring, Ann. Clin. Biochem., 21(6): 519-22, 1984.
2408. Cosofret, V. V., Buck, R. P., A poly(vinylehloride) membrane electrode for determination of phenytoin in pharmaceutical formulations, J. Pharm. Biomed. Anal., 4(l): 45-52, 1986.
2433. Davis, C. M., Fenimore, D. C., Rapid microanalysis of anticonvulsants by high performance thin-layer chromatography, J. Chromatogr., 222: 265-270, 1981.
2489. Fenimore, D. C., Davis, C. M., Simultaneous determination of phenobarbital and diphenylhydantoin in blood plasma by high performance thin layer chromatography, J. High. Resolut. Chroinatogr, Commun., 1: 105-106, 1978.
2545. Godolphin, W., Trepanier, J., Gas chromatography versus irnrnunoassay (EMIT) for analysis of free phenytoin in serum ultrafiltrate, Ther. Drug Monit., 6(3): 374-5, 1984.
2566. Haidukewych, D., Splane, M. L., Vasos, B., Enzyme immunochromatographic assay of phenytoin in capillary and venous blood compared with fluorescence polarization irnmunoassay of plasma from epileptic patients, Clin. Chem., 32(l): 204, 1986.
2582. Hawk, G. L., Franconi, L. C., High-pressure liquid chromatography in quantitation of antiepileptic drugs, Antiepileptic Drugs: Quantitative Analysis and Interpretation, Pipponger, C. E., et al., Eds., Raven Press, New York, 153-62, 1978.
2595. Hinds, J. A., Pincombe, C. F., Smith, S., Duffy, P., The use of a monosaccharide linkage group in a heterologous solid-phase enzyme immunoassay for phenytoin, J. Immunol. Methods, 80: 239-53, 1985.
2596. Hinds, J. A., Pincornbe, C. F., Smith, S., Duffy, P., Ligand displacement immunoassay-demonstration of its use for the measurement of serum phenobarbital and phenytoin, Clin. Chim. Acta, 149(2-3): 105-15, 1985.
2618. Jailkhani, B. L., Jaffery, N. F., Comparison of colorimetric, spectrophotometric, and EMIT methods for estimation of phenytoin., Indian J. Med. Res., 79: 679-683, 1984.
2630. Jones, G. L., Wimbish, C. H., Hydantoins, Handbook of Experimental Pharmacology-Antiepileptic Drugs, Frey, H. H. and Janz, D., Eds., Springer-Verlag, Berlin, 74: 351-419, 1985.
2632. Jones, C. L., Woodbury, D. M., Biochemistry, Handbook of Experimental Pharmacology-Antiepileptic Drugs, Frey, H. H. and Janz, D., Eds., Springer-Verlag, Berlin, 74: 245-263, 1985.
2634. Juergens, U., Routine determination of eight common anti-epileptic drugs and metabolites by high performance liquid chromatography using a column-switching system for direct injection of serum samples, J. Chromatogr., 310(l): 97-106, 1984.
2665. Koizumi, F., Kumai, M., Ishimori, A., Comparison of i-PiT, TDX and EMIT measurement of serum phenytoin and digoxin levels, Rinsho Byori, 33(7): 761-770, 1985.
2677. Kulpmann, W. R., Gey, S., Beneking, M., Kohl, B., Oellerich, M., Determination of total and free phenytoin in serum by non-isotopic immunoassays and gas chromatography, J. Clin. Chem. Clin. Biochem., 22(11): 773-9, 1984.
2755. Mace, P. F., Hughes, J., The Ames Seralyzer Reagent Strip System evaluated for measuring serum phenytoin, Clin. Chem., 32(2): 391, 1986.
2787. Melten, J. W., Wittebrood, A. J., Willems, H. J., Faber, C. H., Werner, J., Faber, D. B., Comparison of equilibrium dialysis, ultrafiltration, and gel permeation chromatography for the determinations of free fractions of phenobarbital and phenytoin, J. Pharm. Sci., 74(6): 692-694, 1985.
2796. Miller, T. D., Pinkerton, T. C., Determinations of free phenytoin in plasma by ultra-filtration and high-performance liquid chromatography, Anal. Chim. Acta, 170(2): 295-300, 1985.
2828. Nishikawa, T., Kubo, H., Saito, M., Competitive nephelometric immunoassay method for antiepileptic drugs in patient blood, J. Immunol. Methods, 29(l): 85-9, 1979.
2843. Oneal, J. S., Sloan, K. B., Schulman, S. C., Substrate-labelled fluorescence immunoassay of phenytoin, J. Pharm. Biomed. Anal., 4(l): 103-6, 1986.
2871. Pippenger, C. E., Bastiani, R. J., Schneider, R. S., Evaluation of an experimental homogeneous enzyme immunoassay for the quantitation of phenytoin and phenobarbitone in serum or plasma, Clinical Pharmacology of Anti-epileptic Drugs, Schneider, H., et al., Eds., Springer-Verlag, New York, 331-41, 1975.
2898. Reeves, S. E., Hanyok, J. J., Amon, S. A., Cooley, P. J., Discrepancy in serum phenytoin concentrations determined by two immunoassay methods in uremic patients., Am. J. Hosp. Pharm., 42: 359-361, 1985.
2937. Schottelius, D. D., Homogeneous immunoassay systern [EMIT] for quantitation of antiepileptic drugs in biological fluids, Antiepileptic Drugs: Quantitative Analysis and Interpretation, Pippenger, C. E., et al., Eds., Raven Press, New York, 95-108, 1978.
2973. Spiehler, V., Sun, L., Miyada, D. S., Sarandis, S. G., Walwick, E. R., Klein, M. W., Jordan, D. B., Jessen, B., Radioimmunoassay, enzyme immunoassay, spectrophotometry and gas-liquid chromatography compared for determination of phenobarbital and diphenylhydantoin, Clin. Chem., 22(6): 749-53, 1976.
3011. Theodore, W. H., Yu, L., Price, B., Yonekawa, W., Porter, R. J., Kapetanovic, I., Moore, H., Kupferberg, H., The clinical value of free phenytoin levels, Ann. Neurol., 18: 90-3, 1985.
3027. Troupin, A. S., Shaw, L. M., A new centrifugal filtration device for free drug separation, Epilepsia, 26(5): 455-9, 1985.
3033. Turley, C. P., Milligan, T., Rapid protein determinations on ultrafiltrates prepared for free phenytoin quantification, Ther. Drug Monit., 7(3): 313-14, 1985.
3059. Wang, S. T., Peter, F., The Abbott TDx fluorescence polarization immunoassay and liquid chromatography compared for five anticonvulsant drug serum, Clin. Chem., 31(3): 493-4, 1985.
3074. Wilson, J. F., Marshall, R. W., Williams, J., Richens, A., Comparison of assay methods used to measure antiepileptic drugs in plasma, Ther. Drug, Monit., 5(4): 449-60, 1983.

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