Fluconazole-induced intoxication with phenytoin in a patient with ultra-high activity of CYP2C9.
OBJECTIVE
The cytochrome P450 enzyme CYP2C9 metabolizes several important drugs, such as warfarin and oral antidiabetic drugs. The enzyme is polymorphic, and all known alleles, for example, CYP2C9*2 and*3, give decreased activity. Ultra-high activity of the enzyme has not yet been reported.


METHODS
We present a patient with Behçet's disease who required treatment with high doses of phenytoin. When fluconazole, a potent inhibitor of CYP2C9, was added to the treatment regimen, the patient developed ataxia, tremor, fatigue, slurred speech and somnolence, indicating phenytoin intoxication. On suspicion of ultra-high activity of CYP2C9, a phenotyping test for CYP2C9 with losartan was performed.


RESULTS
The patient was shown to have a higher activity of CYP2C9 than any of the 190 healthy Swedish Caucasians used as controls.


CONCLUSIONS
Our finding of an ultrarapid metabolism of losartan and phenytoin may apply to other CYP2C9 substrates, where inhibition of CYP2C9 may cause severe adverse drug reactions.
Helldén
Anders
A
Department of Laboratory Medicine, Karolinska Institutet, Division of Clinical Pharmacology, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden. anders.hellden@karolinska.se
Bergman
Ulf
U
Engström Hellgren
Karin
K
Masquelier
Michèle
M
Nilsson Remahl
Ingela
I
Odar-Cederlöf
Ingegerd
I
Ramsjö
Margareta
M
Bertilsson
Leif
L
D000483:Alleles; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism; D000927:Anticonvulsants / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001259:Ataxia / Q000139:chemically induced; D001528:Behcet Syndrome / Q000150:complications; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006970:Disorders of Excessive Somnolence / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D015725:Fluconazole; D006801:Humans; D019808:Losartan / Q000378:metabolism; D008875:Middle Aged; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010641:Phenotype; D010672:Phenytoin / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D013065:Speech Intelligibility / Q000187:drug effects; D014859:Warfarin / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D000927:Anticonvulsants; D004364:Pharmaceutical Preparations; C400322:cytochrome P-450 CYP2C subfamily; D014859:Warfarin; D010672:Phenytoin; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019808:Losartan
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