Involvement of CYP2D6 but not CYP2C19 in nicergoline metabolism in humans.
1. Nicergoline, an ergot derivative previously used as a vasodilator, has gained a new indication in treating the symptoms of senile dementia. 2. Nicergoline is rapidly hydrolysed to an alcohol derivative, 1-methyl-10-alpha-methoxy-9,10-dihydrolysergol (MMDL), which is further N-demethylated to form 10-alpha-methoxy-9,10-dihydrolysergol (MDL). A few individuals display aberrant metabolism of this drug, as shown by their diminished capacity to form the MDL metabolite. The aim of this study was to determine whether defective nicergoline metabolism is associated with the debrisoquine and/or the S-mephenytoin hydroxylation polymorphisms. 3. After a single, oral 30 mg dose of nicergoline, the plasma concentrations of its two metabolites were studied in 15 subjects, divided into three groups with respect to their debrisoquine and S-mephenytoin hydroxylation phenotypes. 4. The pharmacokinetic parameters of MMDL and MDL were similar in the ten subjects who were extensive metabolisers of debrisoquine (five of whom were poor metabolisers of S-mephenytoin) (mean MMDL Cmax 59 nmol l-1 and AUC (0, th) 144 nmol l-1h, mean MDL Cmax 183 nmol l-1 and AUC 2627 nmol l-1h) but were markedly different from the five subjects who were poor metabolisers of debrisoquine (mean MMDL Cmax 356 nmol l-1 and AUC 10512 nmol l-1h, MDL concentrations below limit of quantitation). 5. We conclude that the formation of MDL from MMDL in the metabolism of nicergoline is catalysed to a major extent by CYP2D6 and that the observed interindividual variation in the metabolic pattern of the drug is related to the debrisoquine hydroxylation polymorphism.
Böttiger
Y
Y
Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Huddinge Hospital, Sweden.
Dostert
P
P
Benedetti
M S
MS
Bani
M
M
Fiorentini
F
F
Casati
M
M
Poggesti
I
I
Alm
C
C
Alvan
G
G
Bertilsson
L
L
D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D001794:Blood Pressure / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003647:Debrisoquin / Q000378:metabolism; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008617:Mephenytoin / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009530:Nicergoline / Q000378:metabolism* / Q000494:pharmacology; D010641:Phenotype; D014665:Vasodilator Agents / Q000378:metabolism* / Q000494:pharmacology
D014665:Vasodilator Agents; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D009530:Nicergoline; D008617:Mephenytoin; D003647:Debrisoquin