Possible Gender Effect in Phenytoin Pharmacokinetics in Epilepsy Patients
Abstract number :
3.220
Submission category :
Year :
2000
Submission ID :
2485
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
James C Cloyd, Angela K Birnbaum, Nina M Graves, Ilo E Leppik, Ronald J Sawchuk, Univ of Minnesota, Minneapolis, MN; MINCEP Epilepsy Care, Minneapolis, MN.
Rationale: Gender differences in pharmacokinetics have been reported for drugs that are metabolized by the P450 system. This study examined the possibility of a gender effect with phenytoin (PHT), a 2C9/19 substrate. Methodology: Patients with epilepsy receiving PHT were enrolled in a study to characterize PHT pharmacokinetics. Following a minimum of 11 days on maintenance therapy, blood samples were collected and compliance was assessed on three successive days at approximately the same time after a dose. This procedure was repeated each time the daily dose was changed. A patient completed the study when the desired therapeutic endpoint was achieved or non-compliance was detected. Plasma was analyzed by HPLC. All data are in units of phenytoin sodium. Estimates of Km and Vmax/F were obtained by regression analysis of a plot of total body clearance versus daily dose. The slope of the regression line and the y-intercept were used to determine Km and Vmax/F. Results: Thirty subjects (mean age 33.9?15.3 years) were compliant according to study criteria. There were 18 males (35.0 ?16.0 years) and 12 females (32.3?14.7 years). For each subject, plasma concentrations from two to five different daily doses were used. Data from one male subject was excluded from analysis because the Vmax/F was greater than three standard deviations from the mean. In the remaining 29 patients the Vmax/F was 10.74?3.49 mg/kg/day (females) and 8.26?1.17 mg/kg/day (males)(p?0.05). The Km values were 6.37?2.69 mg/l (females) and 5.72?2.10 mg/l (males). Conclusions: Female patients had higher Vmax/F values than male patients. These results are consistent with previously reported results in younger and elderly adults which show that females take higher doses of PHT than males to achieve similar PHT concentrations. The observed gender effect could arise from differences in absorption, protein binding, and/or metabolism. Studies are underway to confirm this effect and to determine the underlying mechanism. [Supported by NIH NINDS P50-NS16308]