Genetically determined oxidation polymorphism and drug hepatotoxicity. Study of 51 patients.
The influence of genetically determined oxidation polymorphism on drug hepatotoxicity has been poorly investigated and results are controversial. We studied drug oxidation capacity in 51 patients with hepatitis caused mainly by drugs undergoing oxidative metabolism, using dextromethorphan, a test compound recently proposed as a substitute for debrisoquine. Phenotyping was performed using the metabolic ratio (MR) calculated as MR = 0-10 h urinary output of dextromethorphan/0-10 h urinary output of dextrorphan (the main oxidative metabolite), after oral administration of 40 mg dextromethorphan hydrobromide. Dextromethorphan oxidation capacity was similar in patients and in 103 control subjects as judged by: (a) the prevalence of each phenotype (5.9% versus 3.9% for the poor metabolizer phenotype and 94.1% versus 96.1% for the extensive metabolizer phenotype; (b) the frequency distribution histograms of log metabolic ratio; (c) the mean values of dextromethorphan and dextrorphan urinary outputs and of log metabolic ratio for each phenotype. These results show that hepatotoxicity of several drugs, including amineptine, amodiaquine and Plethoryl, is related neither to an impairment in dextromethorphan oxidation capacity nor to an unusually high capacity to oxidize this drug.
Larrey
D
D
Unité de Recherches de Physiopathologie Hépatique (INSERM U24), Hôpital Beaujon, Clichy, France.
Tinel
M
M
Amouyal
G
G
Freneaux
E
E
Berson
A
A
Fouin-Fortunet
H
H
Babany
G
G
Letteron
P
P
Iglicki
F
F
Slama
J L
JL
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D015331:Cohort Studies; D003915:Dextromethorphan / Q000378:metabolism*; D003917:Dextrorphan / Q000652:urine; D005260:Female; D006801:Humans; D007981:Levorphanol / Q000031:analogs & derivatives*; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D010641:Phenotype; D011110:Polymorphism, Genetic
D003917:Dextrorphan; D007981:Levorphanol; D003915:Dextromethorphan