Polymorphic debrisoquine and mephenytoin hydroxylation in patients with pulmonary hypertension of vascular origin after aminorex fumarate.
During the period 1967 to 1971 an increase in the incidence of pulmonary hypertension of vascular origin (PHVO) was observed in Austria, Federal Republic of Germany, and Switzerland. Most patients had been given aminorex fumarate and a possible link was suspected. We therefore investigated the possibility of genetically-determined drug hydroxylation deficiencies (debrisoquine or mephenytoin type) in these patients as an explanation for the development of PHVO. Seventeen patients took 10 mg debrisoquine and 100 mg mephenytoin orally. Sixteen PHVO patients were classified as extensive metabolizers of debrisoquine with logarithmic metabolic ratios of -0.35 +/- 0.11 (mean +/- SEM), whereas one patient was a poor metabolizer with a logarithmic metabolic ratio of 1.82. For the mephenytoin hydroxylation sixteen patients with PHVO were extensive metabolizers, with logarithmic hydroxylation indices of 0.27 +/- 0.05. One poor metabolizer of mephenytoin had a logarithmic hydroxylation index of 1.59. Deficient hydroxylation of debrisoquine and mephenytoin was found in two different patients. The prevalence of poor metabolizers among patients with PHVO after aminorex fumarate was therefore approximately 9% for both debrisoquine and mephenytoin. This corresponds closely to the data of our reference population study where genetic debrisoquine and mephenytoin hydroxylation deficiencies occurred independently, with a prevalence of 10% and 5% respectively. Thus, the normal prevalence of extensive drug hydroxylation phenotypes in patients with PHVO is not consistent with the hypothesis that the development of PHVO after aminorex fumarate might be related to a pharmacogenetically determined impairment of polymorphic drug oxidation.
D000328:Adult; D000368:Aged; D000635:Aminorex / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001067:Appetite Depressants / Q000009:adverse effects* / Q000378:metabolism; D003647:Debrisoquin / Q000378:metabolism*; D005260:Female; D006801:Humans; D006827:Hydantoins / Q000378:metabolism*; D006900:Hydroxylation; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000378:metabolism*; D008297:Male; D008617:Mephenytoin / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D010080:Oxazoles / Q000009:adverse effects*; D010641:Phenotype; D011110:Polymorphism, Genetic; D051381:Rats; D011919:Rats, Inbred Strains
D001067:Appetite Depressants; D006827:Hydantoins; D007546:Isoquinolines; D010080:Oxazoles; D000635:Aminorex; D008617:Mephenytoin; C006559:aminorex fumarate; D003647:Debrisoquin