IMIPRAMINE METABOLISM IN RELATION TO THE SPARTEINE AND MEPHENYTOIN OXIDATION POLYMORPHISMS - A POPULATION STUDY

1 Sparteine and mephenytoin phenotyping tests were carried out in 327 healthy Danish subjects. Two weeks later each subject took 25 mg imipr amine followed by urine collection for 24 h. The urinary content of im ipramine, desipramine, 2-hydroxy-imipramine and 2-hydroxy-desipramine was assayed by h.p.l.c. 2 The medians of the hydroxylation ratios (i.e . 2-hydroxy-metabolite over parent compound) were 6 to 14 times higher in 300 extensive metabolizers of sparteine (EM(s)) as compared with 2 7 poor metabolizers (PM(s)), but none of the ratios separated the two phenotypes completely. 3 There were 324 EM of mephenytoin (EM(M)) and three PM (PM(M)) in the sample. The demethylation ratios between desip ramine, 2-hydroxy-desipramine and their corresponding tertiary amines showed statistically significant correlations with the mephenytoin S/R isomer ratio (Spearman's r(s): -0.20 and -0.27, P < 0.05). 4 The deme thylation ratios were higher in 80 smokers than in 245 non-smokers. Th is indicates that CYP1A2, which is induced by cigarette smoking, also catalyzes the N-demethylation of imipramine. 5 CYP2D6 genotyping was c arried out by PCR in 325 of the subjects, and the D6-wt allele was amp lified in 298 EM(s), meaning that they were genotyped correctly. One P M(s) was D6-wt/D6-B, another PM(s) had the genotype D6-wt/ and hence b oth were misclassified as EM(s). The remaining 25 PM(s) were D6-A/D6-B (n = 5), D6-B/ (n = 18) or D6-D/D6-D (no PCR amplification, n = 2). T hus, the specificity for genotyping PM(s) was 100% and the sensitivity was 92.4%. 6 There were 198 apparently homozygous EM(s) (D6-wt/) and 98 heterozygous EM(s) (D6-wt/D6-A or D6-wt/D6-B). The sparteine metabo lic ratio was lower and the hydroxylation ratios were higher in the ho mozygotes compared with the heterozygotes. However, for all of the rat ios there was a considerable overlap between the two genotypes.