Mephenytoin and sparteine pharmacogenetics in Canadian Caucasians

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Abstract
The frequency of genetically deficient hydroxylation of mephenytoin (M‐defect) was studied in 83 healthy Caucasians living in Toronto. The M‐defect was compared with the widely studied genetic polymorphism of sparteine/debrisoquine oxidations (S‐defect). After ingestion of mephenytoin and sparteine, urine samples (0 to 24 hr) were analyzed for p(4′)‐hydroxymephenytoin and urine samples over 0 to 12 hr were analyzed for sparteine and 2‐and 5‐dehydrosparteine by gas chromatographic methods. Nirvanol, the N‐demethylation product of mephenytoin, was determined by a newly developed gas chromatographic/mass spectrometric method. Frequency distributions of both p‐hydroxymephenytoin and dehydrosparteine excreted in urine were discontinuous (bimodal), while nirvanol and sparteine data were normally distributed. Two poor metabolizers of mephenytoin excreted 2% to 3% of the dose as p‐hydroxymephenytoin and excreted normal amounts of nirvanol, but they were extensive metabolizers of sparteine. Six poor metabolizers of sparteine were found to be extensive metabolizers of mephenytoin (34% to 42% excreted in urine as p‐hydroxymephenytoin). Thus the M‐defect occurs among Canadian Caucasians with a frequency of 2% (0.0% to 7.5% with a confidence limit of 99%) and is independent of the S‐defect. Clinical Pharmacology and Therapeutics (1984) 36, 670–676; doi:10.1038/clpt.1984.238