Effect of age and sex on serum phenytoin concentration in epileptic patients: experience from therapeutic drug monitoring

Shakeel Ahmad Mir


Background: Phenytoin is a widely prescribed anticonvulsant drug. There is a wide interpatient as well as intrapatient variability in serum phenytoin levels despite standard doses. Phenytoin dosing is challenging because the drug exhibits nonlinear kinetics and interacts with a number of drugs. Children metabolize the drug faster as compared to adults. Ageing is also associated with progressive decline in phenytoin clearance. Many CYP450 enzymes show a sex-dependent difference in activity. The objective for this study was to find the effects of sex and ageing on serum phenytoin levels.

Methods: The influence of sex and ageing on the serum phenytoin levels was evaluated retrospectively in 96 anonymized epileptic patients who had received phenytoin alone for more than four weeks. These patients were divided into three age groups, up to 18 years (children), 19-60 years (adults) and more than 60 years (elderly).

Results: There were 6.25% children, 84.37% adults and 9.37% elderly. The majority (71.87%) of patients were males. Children achieved a mean phenytoin level of 15.71±4.85 µg/ml after a daily dose of 225.00±75.82 mg. Adults attained a mean serum phenytoin level of 16.12±3.90 µg/ml with a mean daily dose of 282.72±69.44 mg. The elderly achieved a mean serum phenytoin level of 15.85±2.19µg/ml after a mean daily dose of 266.67±70.71 mg. As compared to 77.77% females, 84.05% males had phenytoin levels in therapeutic range. 50.00% children, 82.71% adults, and 100.00% elderly had phenytoin levels in therapeutic range. There was a correlation between sex, age and serum phenytoin levels (r = 0.003 to 0.762).

Conclusions: There was a correlation between sex, age and serum phenytoin levels in this study. A better understanding of the effects of sex and age on the clinical pharmacology of phenytoin would enhance the quality of prescribing.


Age, Epilepsy, Phenytoin, Serum level, Sex, Therapeutic drug monitoring

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Suthakaran C, Adithan C. Chapter-7 therapeutic drug monitoring- concepts, methodology, clinical applications and limitations. Health Administrator. 2006;19(1):22-6.

Kang JS, Lee MH (2009) Overview of therapeutic drug monitoring. Korean J Intern Med. 2009;24(1):1-10.

Sharma S, Tabassum F, Dwivedi P, Agarwal R, Kushwaha S, Bala K, et al. Critical appraisal of serum phenytoin variation with patient characteristics in a North Indian population. Neurol Ind. 2015;63(2):202-8.

Neuvonen PJ. Bioavailability of phenytoin: clinical pharmacokinetic and therapeutic implications. Clin Pharmacokinet. 1979;4(2):91-103.

Krasowski MD, Penrod LE. Clinical decision support of therapeutic drug monitoring of phenytoin: Measured versus adjusted phenytoin plasma concentrations. BMC Med Inform Decis Mak. 2012;12(1):7.

Offie PS, Sarah HC, Donald RM. Sex Differences in Drug Disposition. J Biomed Biotechnol. 2011; 187103.

Mangoni AA, Jackson SHD. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol. 2003;57(1):6-8.

Acharya JN, Acharya VJ. Epilepsy in the elderly: special considerations and challenges. Ann Indian Acad Neurol. 2014;17(Suppl 1):S18-26.

Houghton GW, Richens A, Leighton M. Effect of age, height, weight and sex on serum phenytoin concentration in epileptic patients. Br J Clin Pharmacol. 1975;2(3):251-6.

Turnbull DM, Rawlins MD, Weightman D, Chadwick DW. "Therapeutic" serum concentration of phenytoin: the influence of seizure type. J Neurol Neurosurg Psychiatry. 1984;47(3):231-4.

Waxman DJ, Holloway MG. Sex differences in the expression of hepatic drug metabolizing enzymes. Molecular Pharmacol. 2009;76(2):215-28.

Kinirons MT, O’Mahony MS. Drug metabolism and ageing. Br J Clin Pharmacol 2004; 57 (5): 540-4

Chu T. Gender differences in pharmakokinectics. US Pharmacist. 2014;39(9):40-3.

O'Malley K, Crooks J, Duke E, Stevenson IH. Effect of age and sex on human drug metabolism. Br Med J. 1971;3(5775):607-9.