Original ArticleThe effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirementvan der Weide, Jana; Steijns, Linda S. W.b; van Weelden, Marga J. M.c; de Haan, Keimpec Author Information aDepartment of Clinical Chemistry, St Jansdal Hospital, Harderwijk, The Netherlands,bDepartment of Clinical Chemistry, Meerkanten GGZ, Ermelo, The Netherlands and cMedical Centre, ′s-Heerenloo-Lozenoord, Ermelo, The Netherlands Received 7 June 2000; accepted 3 November 2000 Correspondence to Dr J. van der Weide, St Jansdal Hospital, Department of Clinical Chemistry, PO Box 138, 3840 AC Harderwijk, The Netherlands Tel: +31 341 463807; fax: +31 341 435533; e-mail: [email protected] Pharmacogenetics 11(4):p 287-291, June 2001. Buy Abstract The cytochrome P450 enzyme CYP2C9 catalyses the metabolism of numerous therapeutic agents, including the anti-epileptic drug phenytoin. CYP2C9 is genetically polymorphic: two allelic variants are known, CYP2C9*2andCYP2C9*3, differing from the wild-type CYP2C9*1by a single point mutation. Both mutant alleles are associated with markedly impaired metabolic capacity for many CYP2C9 substrates compared to the wild-type, resulting in raised serum drug levels upon a given dose. Because this may be relevant in treatment with phenytoin, we studied the effect ofCYP2C9 genotype on phenytoin dose requirement in a group of 60 epileptic patients on long-term phenytoin therapy. CYP2C9genotyping was performed by polymerase chain reaction analysis, phenytoin serum concentrations were measured by high-performance liquid chromatography analysis and related to the maintenance doses. For patients carrying at least one mutantCYP2C9 allele (n= 17), the mean phenytoin dose required to achieve a therapeutic serum concentration was about 37% lower than the mean dose required by wild-type individuals (199 mg/day versus 314 mg/day;P< 0.01). A low maintenance dose (< 200 mg/day) sufficed for 47% of carriers, while 58% of normals required a high dose (> 300 mg/day) for an effective serum level. The results show that there is a strong association between CYP2C9allelic variants and phenytoin dose requirement. Since phenytoin has a narrow therapeutic index and genotyping may be carried out rapidly and at low cost, dosage adjustment based onCYP2C9 genotype, especially at the induction of therapy, would be of value in order to lower the risk of concentration dependent drug intoxications in carriers. © 2001 Lippincott Williams & Wilkins, Inc.