Chemistry, Metabolism and Determination of PHT

The physicochemical properties and pharmacokineties of phenytoin have been extensively reviewed. (See, for example, Refs.) Only a brief summary is given here.

1859. Goldberg, M. A., Phenytoin: binding, Antiepileptic Drugs: Mechanisms of Action, 323-37, Glaser, G. H., Penry, J. K. and Woodbury, D. M., Eds., Raven Press, New York, 1980.
2284. Alvin, J. D., Bush, M. T., Physiological disposition of anticonvulsants, Anticonvulsants, Vida, J. A., Ed., Academic Press, New York, 113-50, 1977.
2364. Browne, T. R., Pharmacologic principles of antiepileptic drug administration, Epilepsy, Diagnosis and Management, Browne, T. R., Feldman, R. G., Eds., Little, Brown & Co., Boston, 145-60, 1983.
2385. Chang, T., Glasko, A. J., Phenytoin: Biotransformation, Antiepileptic Drugs, Woodbury, D. M., et al., Eds., Raven Press, New York, 209-26, 1982.
2631. Jones, C. L., Wimbish, G. H., McIntosh, W. E., Phenytoin: Basic and clinical pharmacology, Med. Res. Rev., 3(4): 383-434, 1983.
2930. Scherber, A., Richter, K., Schaps, P., Distribution of antiepileptic drugs between plasma, plasma water, cerebrospinal fluid, saliva and brain, Epilepsy: a Clinical and Experimental Research, Majkowski, J., Ed., Karger, Basel, 208-12, 1980.
3081. Woodbury, D. M., Metabolites and the mechanisms of action of antiepileptic drugs, Advances in Epileptology, Meinardi, H., Rowan, A. J., Eds., Swets & Zeitlinger, Amsterdam, 134-50,1978.
3085. Woodbury, D. M., Kemp, J. W., Chow, S. Y., Mechanism of action of antiepileptic drugs, Epilepsy, Ward, A. A., et al., Eds., Raven Press, New York, 179-223,1983.

Chemistry and Metabolism

Phenytoin (5,5-diphenylhydantoin, 5,5-diphenyl-2,4-imidazolidinedione) is composed of a five-membered hydantoin ring with two phenyl groups at the five position. PHT has a molecular weight of 256.26 in the free, acid form, and 274.26 as the sodium salt. It is highly lipophilic and can be solubilized in alkali and many organic solvents but, as the free acid, it is poorly soluble in water with a true dissociation constant (pKa) of 8.31. It is 80% nonionized at physiological pH (7.4). The aqueous solubility of phenytoin at pH 7.5 is 21.9 µg/ml at 25'C and, in plasma, the apparent solubility is 75 µg/ml at 37'C due to high plasma protein binding.

Absorbed predominantly from the duo-denum and, to a lesser extent, from the jejunum and ileum, PHT is rapidly and reversibly bound (90% on average) to intra-vascular proteins, especially albumin (see Refs. 440, 788, 916, 1000, 1126, 1232, 1233, 1288, 1314, 1315, 1316, 1393, 1442, 2355). The plasma half-life shows considerable variation from individual to individual (average eighteen hours; range seven to forty-two hours) and may vary within individuals, depending on physiological conditions, such as stress, injury (i.e., burns), pregnancy, viral infections, surgical procedures, and age (see Refs. 2354, 2417, 2522, 2616, 2704, 2706, 2712, 2719, 2970). Both inter-ethnic and interphenotype differences in ability to metabolize PHT have been described (see Refs. 2292, 2336, 2477, 2779, 3086).

440. Loeser, E. W., Jr., Studies on the metabolism of diphenylhydantoin (Dilantin), Neurology, 11: 424-429, 1961.
788. Baggot, J. D. and Davis, L. E., Comparative study of plasma protein binding of diphenylhydantoin, Comp. Gen. Pharmacol., 4: 399-404, 1973.
916. Conard, G. J., Haavik, C. O., and Finger, K. F., Binding of 5,5-diphenylhydantoin and its major metabolite to human and rat plasma proteins, J. Pharm. Sci., 60: 1642-1646, 1971.
1000. Ehrnebo, M., Agurell, S.,Jalling, B., and Boreus, L. O., Age differences in drug binding by plasma proteins: studies on human fetuses, neonates and adults, Europ. J. Clin. Pharmacol., 3: 189-193, 1971.
1126. Hansotia, P. and Keran, E., Ditantin binding by red blood cells of normal subjects, Neurology, 24: 575-578, 1974.
1232. Krasner, J., Drug-protein interaction, Pediat. Clin. N. Amer., 19: 51-63, 1972.
1233. Krasner J.,Giacoia, G.P.,and Yaffe, S.J., Drug protein binding in the newborn infant, Pediat. Res., 7: 317, 1973.
1288. Lightfoot, R. W., Jr., and Christian, C. L., Serum protein binding of thyroxine and diphenylhydantoin, J. Clin. Endocr., 26: 305-308, 1966.
1314. Lund, L., Berlin, A., and Lunde, K. M., Plasma protein binding of diphenylhydantoin in patients with epilepsy, Clin. Phamacol. Ther., 13: 196-200, 1972.
1315. Lunde, K. M., Plasma protein binding of diphenylbydantoin in man, Acia Pharmacol., 29: 152-155, 197 1.
1316. Lunde, K. M., Rane, A., Yaffe, S. J., Lund, L., and Sjoqvist, F., Plasma protein binding of diphenylhydantoin in man, Clin. Pharmacol. Ther., II: 846-855, 1970.
1393. Odar-Cederlof, I. and Borga, O., Kinetics of diphenylhydantoin in uraemic patients: consequences of decreased plasma protein binding, Europ. J. Clin. Phartnacol., 7: 31-37, 1974.
1442. Rane, A., Lunde, P. K. M., Jalling, B., et al., Plasma protein binding of diphenylhydantoin in normal and hyperbilirubinemic infants, Epilepsy Abstracts, 4: 223, 1971.
2355. Brodie, M. J., Muir, S. E., Agnew, E., Macphee, C. Volo, C., Teasdale, E., Macpherson, P., Protein binding and CSF penetration of phenytoin following acute oral dosing in man, Br. J. Clin. Pharmac., 19(2): 161-8, 1985.
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.
2417. Crooks, J., O’Malley, K., Stevenson, I. H., Pharmacokinetics in the elderly, Handbook of Clinical Pharmacokinetics, Gibaldi, M., Prescott, L., Eds., ADIS Health Science Press, New York, 169-87,1983.
2522. Gambertoglio, J. G., Effects of renal disease: altered pharmacokineties, Pharmacokinetic basis for drug treatment, Benet, L. Z., Ed., Raven Press, New York, 149-71, 1984.
2616. Jacknowitz, A. I., Possible effect of viral infections on drug metabolism, JAMA, 251(16): 2084-5, 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.
2712. Levy, G., Protein binding of drugs in the maternal-fetal unit and its potential clinical significance, Drugs and Pregnancy. Maternal Drug Handling-Fetal Drug Exposure, Krauer, B., et al., Eds., Academic Press, Orlando, 29-44, 1984.
2719. Liponi, D. F., Winter, M. E., Tozer, T. N., Renal function and therapeutic concentrations of phenytoin, Neurology, 34: 395-7, 1984.
2970. Sonnenfeld, G., Harned, C. L., Nerland, D. E., Effects of interferon on drug metabolism, Tex. Rep. Biol. Med., 41: 363-9, 1981.
2292. Andoh, B., Idle, J. R., Sloan, T. P., Smith, R. L., Woolhouse, N., Interethnic and inter-phenotype differences among Ghanaians and Caucasians in the metabolic hydroxylation of phenytoin, Br. J. Clin. Pharmacol., 9: 282-83, 1979.
2336. Billings, R. E., Hansen, D. K., Species differences in phenytoin induction of cytochrome P450 due to pharmacokinetic differences, Proc. West Pharmacol. Soc., 27: 539-42, 1984.
2477. Eichelbaum, M., Genetic polymorphism of oxidative drug metabolism. Therapeutic and toxicologic implications, Internist, 24: 117-127, 1983.
2779. McClanahan, J. S., Maguire, J. H., Human stereoselective production of phenytoin (5,5-diphenylhydantoin) dihydrodiol and phenol metabolites, Pharmacologist, 27(3): 148, 1985.
3086. Woolhouse, N. M., Adjepon-Yamoah, K. K., Critchley, A., Prescott, L. F., Reduced capacity for diphenylhydantoin hydroxylation in Ghanaians, Br. J. Clin. Pharmacol. 18(2): 287p-8p, 1984.

Less than 5% of phenytoin is excreted unchanged in the urine. Metabolism is by hepatic microsomal enzymes and the major metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) is not active. Arene oxide and epoxide intermediates have been described. See Refs.

69. Cucinell, S. A., Factors affecting drug metabolism, Bull. N.Y. Acad. Med., 42: 324, 1966.
179. Jensen, B. N. and Grynderup, V., Studies on the metabolism of Phenytoin, Epilepsia, 7: 238-245, 1966.
205. Kutt, H., Haynes, J., and McDowell, F., The effect of phenobarbital upon diphenyihydantoin metabolism in man, Neurology, 15: 274-275, 1965.
269. Noach, E. L., Woodbury, D. M., and Goodman, L. S., Studies on the absorption, distribution, fate and excretion of 4-C14-labeled diphenylhydantoin, J. Pharm. Exp. Ther., 122: 301-314, 1958.
284. Petty, W. C. and Karler, R., The influence of aging on the activity of anti-convulsant drugs, J. Pharm. Exp. Ther., 150: 443-448, 1965.
359. Toman, J. E. P., Drugs effective in convulsive disorders, The Pharmacological Basis of Therapeutics, 3rd Ed., 215-224, Goodman, L. S., Gilman, A., Eds., Macmillan, New York, 1965.
361. Triedman, H. M., Fishman, R. A., and Yahr, M. D., Determination of plasma and cerebrospinal fluid levels of Dilantin in the human, Trans. Amer. Neurol. Assn., 85: 166-170, 1960.
440. Loeser, E. W., Jr., Studies on the metabolism of diphenylhydantoin (Dilantin), Neurology, 11: 424-429, 1961.
442. Burns, J. J. and Conney, A. H., Enzyme stimulation and inhibition in the metabolism of drugs, Proc. Roy. Soc. Med., 58: 955-960, 1965.
443. Butler, T. C., The metabolic conversion of 5,5-diphenylhydantoin to 5-(p-hydroxyphenyl)-5-phenylhydantoin, Pharm. Exp. Ther., 119: 1-11, 195 7.
444. Maynert, E. W., The metabolic fate of diphenylhydantoin in the dog, rat and man, J. Pharm. Exp. Ther., 130: 275-284, 1960.
445. Chang, T., Baukema, J., Dill, W. A., Buchanan, R. A., Goulet, J. R., and Glazko, A. J., Metabolic disposition of diphenylhydantoin (DPH) in human subjects following intravenous administration, Clin. Res., 16: 464, 1968.
446. Svensmark, O., Schiller, P. J., and Buchthal, F., 5, 5-diphenylhydantoin (Dilantin) blood levels after oral or intravenous dosage in man, Acta Pharmacol. (Kobenhavn), 16: 331-346, 1960.
452. Kutt, H., Verebely, K., and McDowell, F., Inhibition of diphenylhydantoin metabolism in rat liver microsomes by antituberculosis drugs, Neurology, 17: 318-319, 1967.
453. Kutt, H., Verebely, K., and McDowell, F., Inhibition of diphenylhydantoin metabolism in rats and in rat liver microsomes by antitubercular drugs, Neurology, 18: 706-710, 1968.
521. Porter, I. H., The genetics of drug susceptibility, Dis. Nerv. Syst., 27: 25-36, 1966.
528. Gerber, N. and Arnold, K., The effect of diphenyl-piperazine compounds and other agents on diphenylhydantoin, zoxazolamine and hexobarbital metabolisms. Pharm. Exp. Ther., 164: 232-238, 1968.
544. Burns, J. J., Cucinell, S. A., Koster, R., and Conney, A. H., Application of drug metabolism to drug toxicity studies, Ann. N.Y. Acad. Sci., 123: 273-286, 1965.
553. Kutt, H., Haynes, J., and McDowell, F., Some causes of ineffectiveness of diphenylhydantoin, Arch. Neurol., 14: 489-492, 1966.
554. Kutt, H., Winters, W., Scherman, R., and McDowell, F., Diphenylhydantoin and phenobarbital toxicity, Arch. Neurol., 11: 649-656, 1964.
555. Kutt, H., Winters, W., Kokenge, R., and McDowell, F., Diphenylhydantoin metabolism, blood levels, and toxicity, Arch. Neurol., 11: 642-648, 1964.
1044. Gabler, W. L. and Hubbard, G. L., The metabolism of 5,5-diphenylhydantoin (DPH) in nonpregnant and pregnant Rhesus monkeys, Arch. Int. Pharmacodyn., 203: 72-91, 1973.
1051. Garrettson, L. K., Pharmacology of anticonvulsants, Pediat. Clin. N. Amer., 19: 179-191, 1972.
1076. Glazko, A. J. and Chang, T., Diphenylhydantoin, absorption, distribution and excretion, Antiepileptic Drugs, 127-136, Woodbury, D. M., Penry, J. K., and Schmidt, R. P., Eds., Raven Press, New York, 1972.
1247. Kutt, H., Biochemical and genetic factors regulating Dilantin metabolism in man, Ann. N.Y. Acad. Sci., 179: 704-722, 1971.
1669. Weber-Eggenberger, S. and Kaufmann, G., Studies on absorption, elimination and antiarrhythmic serum concentrations of diphenylhydantoin (antisacer) in digitalized heart patients, Z. Kreislaufforsch., 60: 420-432, 1971.
1697. Woodbury, D. M. and Swinyard, E. A., Diphenylhydantoin, absorption, distribution, and excretion, Antiepileptic Drugs, 113-123, Woodbury, D. M., Penry, J. K., and Schmidt, R. P., Ed.%., Raven Press, New York, 1972.
1859. Goldberg, M. A., Phenytoin: binding, Antiepileptic Drugs: Mechanisms of Action, 323-37, Glaser, G. H., Penry, J. K. and Woodbury, D. M., Eds., Raven Press, New York, 1980.
2284. Alvin, J. D., Bush, M. T., Physiological disposition of anticonvulsants, Anticonvulsants, Vida, J. A., Ed., Academic Press, New York, 113-50, 1977.
2334. Billings, R. E., Interactions between folate metabolism, phenytoin metabolism and liver microsomal cytochrome P450, Drug. Nutr. Interact., 3(l); 21-32, 1984.
2335. Billings, R. E., Fischer, L. J., Oxygen-18 incorporation studies of the metabolism of phenytoin to the catechol, Drug Metab. Dispos., 13(3): 312-17, 1985.

2336. Billings, R. E., Hansen, D. K., Species differences in phenytoin induction of cytochrome P450 due to pharmacokinetic differences, Proc. West Phartnaeol. Soc., 27: 539-42, 1984.
2337. Billings, R. E., Milton, S. G., Chemical nature of reactive metabolites formed with phenytoin in rat liver microsomes, Fed. Proc., 44(4): 1114, 1985.
2364. Browne, T. R., Pharmacologic principles of antiepileptic drug administration, Epilepsy, Diagnosis and Management, Browne, T. R., Feldman, R. G., Eds., Little, Brown & Co., Boston, 145-60, 1983.
2385. Chang, T., Glasko, A. J., Phenytoin: Biotransformation, Antiepileptic Drugs, Woodbury, D. M., et al., Eds., Raven Press, New York, 209-26, 1982.
2395. Claesen, M., Moustafa, M. A., Adline, J., Vandervorst, D., Poupaert, J. H., Evidence for an arene oxide-NIH shift pathway in the metabolic conversion of phenytoin to 5-(4-hydroxyphenyl)-5-Phenylhydantoin in the rat and in man, Drug Metab. Dispos., 10(6): 667-71, 1982.
2587. Heinicke, R. J., Stobs, S. J., Al-Turk, W., Lemon, H. M., Chronic phenytoin administration and the hepatic mixed function oxidase system in female rats, Gen. Pharmacot., 15(2): 85-9, 1984.
2631. Jones, C. L., Wimbish, G. H., McIntosh, W. E., Phenytoin: Basic and clinical pharmacology, Med. Res. Rev., 3(4): 383-434, 1983.
2684. Lai, M. L., Hung, T. P., Pharmacokineties of a large single dose phenytoin, J. Formosan Med. Assoc., 82: 370-80, 1983.
2779. McClanahan, J. S., Maguire, J. H,, Human stereoselective production of phenytoin (5,5-diphenylhydantoin) dihydrodiol and phenol metabolites, Pharmacologist, 27(3): 148, 1985.
2810. Moustafa, M. A., Claesen, M., Adline, J., Vandervorst, D., Poupaert, J. H., Evidence for an arene-3,4-oxide as a metabolic intermediate in the meta- and para-hydroxylation of phenytoin in the dog, Drug Metab. Dispos., 11(6): 574-80, 1983.
2873. Pirttiaho, H. I., Sotaniemi, E. A., Pelkonen, R. O., Pitkanen, U., Hepatic blood flow and drug metabolism in patients on enzyme-inducing anticonvulsants, Eur. J. Clin. Pharmacol., 22: 441-5,1982.
2930. Scherber, A., Richter, K., Schaps, P., Distribution of antiepileptic drugs between plasma, plasma water, cerebrospinal fluid, saliva and brain, Epilepsy: a Clinical and Experimental Research, Majkowski, J., Ed., Karger, Basel, 208-12, 1980.
3081. Woodbury, D. M., Metabolites and the mechanisms of action of antiepileptic drugs, Advances in Epileptology, Meinardi, H., Rowan, A. J., Eds., Swets & Zeitlinger, Amsterdam, 134-50, 1978.
3083. Woodbury, D. M., Phenytoin: Mechanisms of Action, Antiepileptic Drugs, Woodbury, D. M., Penry, J. K., Pippinger, C. E., Eds., Raven Press, New York, 269-81, 1982.

At the organ or system level, PHT has been reported to have wide distribution in brain, liver, muscle and fat, as measured in various species. Most of the tissue PHT is in bound form. Free PHT is found in all transcellular fluids including cerebrospinal fluid, saliva, semen, milk, gastrointestinal fluid and bile.

Levels of PHT in the brain are one to three times those of total (free and bound) drug in plasma and six to ten times those of free drug in plasma. In humans, the brain/ plasma ratio for PHT averages 1.52, although white matter (at 1.73) contains more than gray matter. (See Refs. 101, 267, 269, 531, 794, 862, 1082, 1215, 1383, 1471, 1539, 1687, 1704, 2310, 2892.) Brain tumor tissue seems to take up even more (see Refs. 400, 2959). The suggestion has been made that depolarized or rapidly firing cells bind more phenytoin.

101. Firemark, H., Barlow, C. F., and Roth, L. J., The entry, accumulation and binding of diphenylhydantoin-2-C14 in brain: studies on adult, immature and hypercapnic cats, Int. J. Neuropharmacol, 2: 25-38, 1963.
267. Nakamura, K., Masuda, Y., Nakatsuji, K., and Hiroka, T., Comparative studies on the distribution and metabolic fate of diphenylhydantoin and 3-ethoxycarbonyl-diphenylhydantoin (P-6127) after chronic administrations to dogs and cats, Naunyn- Schmiedeberg Arch. Pharm., 254: 406-417, 1966.
269. Noach, E. L., Woodbury, D. M., and Goodman, L. S., Studies on the absorption, distribution, fate and excretion of 4-C14   labeled diphenylhydantoin, J. Pharm. Exp. Ther., 122: 301-314, 1958.
531. Kemp, J. W. and Woodbury, D. M., Intracellular distribution of 4- C14 diphenylhydantoin (Dilantin) in rat brain, Pharmacologist, 4: 159, 1962.
794. Barlow, C. F., Diphenylhydantoin-2-C14 in cat brain, J. Neuropath. Exp. Neurol., 22: 348-349, 1965.
862. Boykin, M. E., In vivo and in vitro association of 5, 5-diphenylhydantoin with brain subtractions, Neurology, 4: 392-393, 1974.
1082. Goldberg, M. A. and Todoroff, T., Diphenylhydantain binding to brain fractions, Neurology, 22: 410, 1972.
1215. Kemp, J. W. and Woodbury, D. M., Subcellular distribution of 4-14C -diphenylhydantoin in rat brain, J. Pharmacol. Exp. Ther., 177: 342-349, 1971.
1383. Nielsen, T. and Cotman, C., The binding of diphenylhydantoin to brain and subcellular fractions, Europ. J. Pharmacol., 14: 344-350, 1971.
1471. Rizzo, M., Morselli, P. L. and Garattini, S., Further observations on the interactions between phenobarbital and diphenylhydantoin during chronic treatment in the rat, Biochem. Pharmacol., 21: 449-454, 1972.
1539. Sherwin, A. L., Eisen, A. A. and Sokolowski, C. D., Anticonvulsant drugs in human epileptogenic brain, Presented at the annual meeting of the American Neurological Association and the Canadian Congress of Neurological Sciences, Montreal, 1973.
1687. Wilensky, A. J. and Lowden, J. A., Interaction of diphenylhydantoin 414C with subcellular fractions of rat brain, Epilepsy Abstracts, 5: 194, 1972.
1704. Yanagihara, T., Distribution of diphenylhydantoin in the neuronal and glial fractions, Antiepileptic Drugs, 125-126, Woodbury, D. M., Penry, J. K., and Schmidt, R. P., Eds., Raven Press, New York, 1972.
2310. Baron, J. C., Roeda, D., Munari, C., Crouzel, C., Chodkiewics, J. P., Comar, D., Brain regional pharmacokinctics of 11C-labeled diphenylhydantoin: positron emission tomography in humans, Neurology, 3-3: 580-5, 1983.
2892. Rapport, R. L., Harris, A. B., Friel, P. N., Ojemann, G. A., Human epileptic brain: Na, K, ATPase activity and phenytoin concentrations, Arch. Neurol., 32(8); 549-54, 1975.
400. Rosenblum, I. and Stein, A. A., Preferential distribution of diphenylhydantoin in primary human brain tumors, Biochem. Pharmacol., 12: 1453-1454, 1963.
2959. Sironi, V. A., Ravagnati, L., Ettorre, C., Cabrini, G. P., Marossero, F., Differences between the concentrations of antiepileptic drugs in normal and pathological human brain, Eur. J., Clin. Pharmacol., 22; 447-9, 1982.

At cellular and subcellular levels, neurons appear to bind more PHT than glia. Nuclear, mitochondrial and microsomal fractions all bind PHT, apparently non-specifically. Studies of protein binding indicate that brain tissue binding correlates with protein concentration, cations, temperature and ionic strength, thus fulfilling the criteria for nonspecific binding. However, there is some evidence for specific binding. See Refs:

1863. Goldberg, M. A., Todoroff, T. and Crandall, P., Phenytoin binding to human brain, Neurology, 27(4): 374, 1977.
2351. Bowling, A. C., De Lorenzo, R. J., Micromolar affinity benzodiazepine receptors: indentification and characterization in central nervous system, Science, 216: 1247-50, 1982.
2369. Burnham, W. N., Spero, L., Okazaki, M. M., Madras, B. K., Saturable binding of [3H]-phenytoin to rat brain membrane fraction, Can. J. Physiol. Pharmacol., 59(4): 402-7,1981.
2797. Mimaki, T., Deshmukh, P. P., Yamamura, H. I., Effect of phenytoin on benzodiazepine receptors in rat brain, Advances in Epileptology: 12th Epilepsy International Symposium, Dam, M., et al., Eds., Raven Press, New York, 73-9, 1981.
2829. Nishimura, S., Imazawa, M., Miyamoto, K., Possible existence of loosely membrane-bound specific binding sites for phenytoin, Folia Psychiatr. Neurol. Jpn., 37(3): 303-5, 1983.
2947. Shah, D. S., Chambon, P., Guidotti, A., Binding of [3H]-5,5 Diphenythydantoin in rat brain membranes, Neuropharmacology, 20; 1115-9, 1981.

PHT also binds to lipids. Total brain lipid mixtures have the greatest activity, while those obtained by extraction of subcutaneous fat (chloroform-methanol extraction) show no binding of tritiated PHT (see Refs. 1860, 1861, 1862, 1863, 2547). All of the phospholipids show some degree of PHT binding, while gangliosides, cholesterol, cerebrosides and other natural lipids have no binding activity. Among the phospholipids, dipalmitoyl and dioleoyl lecithins have the greatest binding activity (80%). Since PHT binds to both phospholipids and protein, the potential for lipid-PHT-lipid, protein-PHT-lipid, and protein-PHT-protein binding exists. Consistent with this, PHT-induced alterations in membrane fluidity have been documented.

1860. Goldberg, M. A., Phenytoin, phospholipids and calcium, Neurology, 27: 827-33, 1977.
1861. Goldberg, M. A. and Crandall, P. H., Human brain binding of phenytoin, Neurology, 28: 881-5, 1978.
1862. Goldberg, M. A. and Todoroff, T., Phenytoin binding to brain phospholipids, Neurology, 26: 386, 1976.
1863. Goldberg, M. A., Todoroff, T. and Crandall, P., Phenytoin binding to human brain, Neurology, 27(4): 374, 1977.
2547. Goldberg, M. A., The Pharmacology of Phenytoin, H. Houston Merritt Memorial Volume, Yahr, M.D., Ed., Raven Press, New York, 81-99, 1983.

See also Refs.

3716. Shorvon, S.D., Is there a therapeutic range for phenytoin? in: Fifty Years of Phenytoin, International Congress and Symposium Series Number 120, Dam, M. & Richens, A., eds., Royal Society of Medicine Services, London, 13-8,1987.

3717. Umstead, G.S., and Neumann, K.H., Correlation of free phenytoin to serum albumin in cancer patients, DICP, 24: 923-926, 1990.

3718. Rambeck, B., Schnabel, R., May, T., Jurgens, U., and Villagran, R., Postmortem concentrations of phenytoin in different regions of the brain and in the serum: analysis of autoptic specimens from 24 epileptic patients, Ther. Drug Monit., 14: 27-35, 1992.

3719. Kaplan, B., and Krumlovsky, F.A., Phenytoin in end-stage renal disease, Int. J. Artif. Organs, 15(2): 69-70, 1992.

3720. Hayes, G., and Kootsikas, M.E., Reassessing the lower end of the phenytoin therapeutic range: a review of the literature, Ann. Pharmacother, 27(11):1389-92, 1993.

3721. Scheyer, R.D., During, M.J., Hochholzer, J.M., Spencer, D.D., Cramer, J.A., and Mattson, R.H., Phenytoin concentrations in the human brain: an in vivo microdialysis study, Epilepsy Res., 18(3):227-32, 1994.

3722. Wilder, B.J., Use of parenteral antiepileptic drugs and the role of fosphenytoin, Neurology, 46(SUPP1):S1-2, 1996.

3723. Browne, T.R., Kugler, A.R., and Eldon, M.A., Pharmacology and pharmacokinetics of fosphenytoin, Neurology, 46(SUPP1):S3-7, 1996.

3724. Luer, M.S., Fosphenytoin, Neurol. Res., 20:178-182, 1998.

3725. Ramsay, R.E., Wilder, B.J., Uthman, B.M., Garnett, W.R., Pellock, J.M., Barkley, G.L., Leppik, .I.E., and Knapp, L.E., Intramuscular fosphenytoin (cerebyx R) in patients requiring a loading dose of phenytoin, Epilepsy Res., 28:181-187, 1997.

3726. Dasgupta, A., Datta, P., Redlich, G., and Limmany, A., Analytical performance of a new chemiluminescent phenytoin (ACS:180) assay, Ther. Drug Monit.,19:191-194, 1997.

3727. Eadie, M.J., Therapeutic drug-monitoring - antiepileptic drugs, Br. J. Pharmacol., 46:185-193, 1998.

3728. Frame, B., and Beal, S.L., Non-steady state population kinetics of intravenous phenytoin, Ther. Drug Monit., 20:408-416, 1998.

3729. Kodama, H., Kodama, Y., Shinozawa, S., Kanemaru, R., Todaka, K., and Mitsuyama, Y., Serum protein binding kinetics of phenytoin in monotherapy patients, J. Clin. Pharm. Ther., 23:361-365, 1998.

3730. Takeoka, M., Krishnamoorthy, K.S., Soman, T.B., and Caviness, V.S., Fosphenytoin in infants, J. Child Neurol., 13(11):537-540, 1998.

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