Effect of dose on phenytoin absorption.

To determine the effect of dose on phenytoin bioavailability, a single intravenous 15-mg/kg dose, single oral doses of 400, 800, and 1,600 mg, and 1,600 mg in divided doses (400 mg every 3 hr) were given to six healthy male subjects. Values of Vmax (maximum elimination rate) and Km (serum concentration at which rate of elimination is one half the maximum rate) from the intravenous dose were used to determine the extent of absorption. Although no statistically significant difference in extent of phenytoin absorption was detected, the time to reach maximum phenytoin serum concentrations increased from 8.4 hr for the 400-mg dose and 13.2 hr for the 800-mg dose to 31.5 hr for the 1,600-mg dose. After the 400, 800, and 1,600-mg doses and 1,600-mg divided doses, the serum concentration peaks were 3,9, 5.7, 10.7, and 15.3 mg/l. It is suggested that the prolonged, but complete, absorption of large phenytoin doses is due to slow dissolution and continued absorption from the colon. Due to prolonged absorption of phenytoin, it may be necessary to use larger oral than intravenous loading doses to achieve the same maximum phenytoin serum concentrations.