Phenytoin pharmacokinetics in critically ill trauma patients

Abstract

Preliminary data have suggested that phenytoin systemic clearance may increase during initial therapy in critically ill patients. The objectives for this study were to model the time-variant phenytoin clearance and evaluate concomitant changes in protein binding and urinary metabolite elimination. Phenytoin was given as an intravenous loading dose of 15 mg/kg followed by an initial maintenance dose of 6 mg/kg/day in 10 adult critically ill trauma patients. Phenytoin bound and unbound plasma concentrations were determined in 10 patients and urinary excretion of the metabolite p-hydroxyphenyl phenylhydantoin (p-HPPH) was measured in seven patients for 7 to 14 days. A Michaelis-Menten one-compartment model incorporating a time-variant maximal velocity (Vmax) was sufficient to describe the data and superior to a conventional time-invariant Michaelis-Menten model. Vmax for the time-variant model was defined as V'max + Vmax delta (1 - e(-kindt)). Vmax infinity is the value for Vmax when t is large. The median values (ranges) for the parameters were Km = 4.8 (2.6 to 20) mg/L, Vmax infinity = 1348 (372 to 4741) mg/day, and kind = 0.0115 (0.0045 to 0.132) hr-1. Phenytoin free fraction increased in a majority of patients during the study period, with a binding ratio inversely related to albumin. Measured urinary p-HPPH data were consistent with the proposed model. A loading and constant maintenance dose of phenytoin frequently yielded a substantial, clinically significant fall in plasma concentrations with a pattern of apparently increasing clearance that may be a consequence of changes in protein binding, induction of metabolism, or the influence of stress on hepatic metabolic capacity.

Continuous venovenous hemodiafiltration trace element clearance in pediatric patients: a case series

“…For example, acute inflammation alters alpha-2 globulin expression and other trace element binding proteins [23]. Certain drugs also exhibit lower plasma protein binding rates in patients with critical illness and renal failure than in healthy individuals [25,26].…”

Pharmacokinetics of Tirilazad and U-89678, an Active, Reduced Metabolite, following Acute Head Trauma in Adults.

“…This is supported by the fact that the median apparent clearance of tirilazad in head-injured patients not receiving anticonvulsants in the present study (0.258 L/h/kg) is somewhat lower than that observed previously in healthy male volunteers at the same dose level (0.352 L/h/kg). 15 Previous work by Boucher et al 17,18 suggests that the clearances of antipyrine and phenytoin were increased following acute neurotrauma. In the present study, tirilazad clearance did not appear to be induced following acute head trauma.…”

“…Serial (prior to the dose, at the end of the infusion, and 1, 3, and 5 h after infusion start) venous blood samples (5 mL) were collected after the first or second dose and after one of the doses on the last dosing day (doses [17][18][19][20]. Nadir samples were also collected on days 2-4.…”

“…14 Tirilazad is apparently cleared more rapidly in women than men, 15 and tirilazad clearance is reduced approximately 30% in the elderly. 16 Acute neurotrauma has been reported to affect the pharmacokinetics of phenytoin 17 and antipyrine. 18 In both cases, the metabolism of these cytochrome P-450 substrates appears to be induced after neurotrauma.…”

Phenytoin pharmacokinetics after intravenous administration to patients receiving enteral tube feeding

“…The increase in Vma x in group 2 could be due to metabolic induction, as has been suggested in a case report of a patient with low phenytoin concentrations who was receiving total parenteral nutrition [28] and as is also suggested by the metabolite data of the current study. Results of another study have shown increased estimates of Vma x for phenytoin in critically ill patients [29]. It was suggested that changes in protein binding, induction of hepatic metabolism or stressrelated transient increases in hepatic function could all possibly play a part in the increased elimination rate of phenytoin.…”