where phenytoin concentrations are in micrograms per milliliter and albumin concentration is in grams per deciliter. METABOLISM
Following absorption and distribution, only 4 to 5 percent of phenytoin is excreted unchanged in the urine. The remainder is metabolized by hepatic microsomal enzymes. The drug is primarily hydroxylated to a series of inactive compounds. The major (60 to 70 percent) metabolite is the parahydroxyphenyl derivative. It is glucuronidated, secreted in the bile, reabsorbed, and subsequently excreted in the urine. Phenytoin is not appreciably removed by hemodialysis or hemoperfusion. The metabolism of phenytoin is capacity limited (dose dependent). At plasma concentrations below 10 pg/mL, elimination is first order (a fixed percentage of drug metabolized per unit of time). However, at higher concentrations, including those in the therapeutic range (10 to 20 pg/mL), the metabolic pathways may become saturated, and the elimination may change to zero-order kinetics (a fixed amount metabolized per unit of time). This change in kinetics can markedly prolong the half-life of phenytoin, which is normally 6 to 24 h. An understanding of capacity-limited kinetics is essential to the proper dosing of phenytoin, the avoidance of side effects with chronic therapy, and the management of overdoses. At higher levels in the therapeutic range, any increase in the daily dose may result in a disproportionate increase in the plasma level. Thus, incremental doses should be limited to 30 mg and levels should be carefully monitored when it is necessary to raise phenytoin doses above 300 mg (about 5 mg/kg) per day.
Because phenytoin's half-life is 24 h or less, once-a-day regimens may result in erratic levels and become problematic for patients requiring tight control. Only one phenytoin preparation (Phenytoin Kapseals) is approved by the Food and Drug Administration for once-a-day use. Concomitant use of drugs that either inhibit or enhance hepatic microsomal activity may result in an increase or decrease of phenytoin level, respectively. Phenytoin also affects the metabolism of various other agents (Iable,,,,17,2,:1).
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