INVOLVEMENT OF CYP2D6 BUT NOT CYP2C19 IN NICERGOLINE METABOLISM IN HUMANS

1 Nicergoline, an ergot derivative previously used as a vasodilator, h as gained a new indication in treating the symptoms of senile dementia . 2 Nicergoline is rapidly hydrolysed to an alcohol derivative, 1-meth yl-10-alpha-methoxy-9,10-dihydrolysergol (MMDL), which is further N-de methylated to form 10-alpha-methoxy-9,10-dihydrolysergol (MDL). A few individuals display aberrant metabolism of this drug, as shown by thei r diminished capacity to form the MDL metabolite. The aim of this stud y was to determine whether defective nicergoline metabolism is associa ted with the debrisoquine and/or the S-mephenytoin hydroxylation polym orphisms. 3 After a single, oral 30 mg dose of nicergoline, the plasma concentrations of its two metabolites were studied in 15 subjects, di vided into three groups with respect to their debrisoquine and S-mephe nytoin hydroxylation phenotypes. 4 The pharmacokinetic parameters of M MDL and MDL were similar in the ten subjects who were extensive metabo lisers of debrisoquine (five of whom were poor metabolisers of S-mephe nytoin) (mean MMDL C-max 59 nmol l(-1) and AUC (0, th) 144 nmol l(-1) h, mean MDL C-max 183 nmol l(-1) and AUC 2627 nmol l(-1) h) but were m arkedly different from the five subjects who were poor metabolisers of debrisoquine (mean MMDL C-max 356 nmol l(-1) and AUC 10512 nmol l(-1) h, MDL concentrations below limit of quantitation). 5 We conclude tha t the formation of MDL from MMDL in the metabolism of nicergoline is c atalysed to a major extent by CYP2D6 and that the observed interindivi dual variation in the metabolic pattern of the drug is related to the debrisoquine hydroxylation polymorphism.