Effect of barbiturate therapy on phenytoin pharmacokinetics.
OBJECTIVE
To evaluate the effect of high-dose pentobarbital therapy on phenytoin pharmacokinetics.


METHODS
A prospective, clinical study.


METHODS
The intensive care unit of a university hospital.


METHODS
Ten adult patients with cerebral lesions requiring anticonvulsants and control of intracranial pressure.


METHODS
Each patient received phenytoin sufficient to maintain a plasma concentration at 15 micrograms/mL (60 mumol/L) both before and after barbiturate therapy. Plasma concentrations of total phenytoin, unbound phenytoin, and the major metabolite of phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin, were measured, and pharmacokinetic variables obtained before and after barbiturate therapy were compared.


RESULTS
Plasma concentrations of total phenytoin remained within the therapeutic range during the 12-hr period preceding barbiturate therapy. After barbiturate therapy, plasma concentrations of both total and unbound phenytoin were significantly less than those concentrations before barbiturate therapy. For total phenytoin, maximum metabolic velocity was increased by 62% (1.09 +/- 0.62 to 1.77 +/- 0.52 mg/L/hr, 1.20 +/- 0.68 to 1.95 +/- 0.57 nmol/L/sec, p < .05), and area under the plasma concentration-time curve (0 to infinity) and mean residence time were each decreased by 73% (32.5 +/- 20.0 to 8.7 +/- 3.1 min.mg/mL, 2.14 +/- 1.25 to 0.57 +/- 0.19 sec.mmol/L, p < .01, and 135,000 +/- 69,000 to 37,000 +/- 11,000 secs, p < .005, respectively) after barbiturate therapy. The plasma concentration of the principal metabolite of phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin, was significantly increased after barbiturate therapy.


CONCLUSIONS
Phenytoin metabolism is increased by barbiturate therapy, and supplemental doses of phenytoin and frequent drug monitoring may be required after barbiturate therapy.
Yoshida
N
N
Department of Anesthesiology and Intensive Care Medicine, Osaka City University Medical School, Japan.
Oda
Y
Y
Nishi
S
S
Abe
J
J
Kaji
A
A
Asada
A
A
Fujimori
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016638:Critical Illness; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D006801:Humans; D007427:Intracranial Pressure / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010424:Pentobarbital / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010672:Phenytoin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011446:Prospective Studies
D010672:Phenytoin; D010424:Pentobarbital