Differences in organ distribution of methylene blue are mainly responsible for the different pharmacokinetics after oral and i.v. administration. If methylene blue acts in the liver, where ifosfamide is primarily activated to reactive and potentially toxic metabolites, oral and i.v. methylene blue are likely to be equally effective. However, if the site of action is the central nervous system, i.v. methylene blue which results in much higher concentrations in brain seems preferable.

Dextromethorphan hydrobromide, 25 mg po, was given to 268 unrelated Swiss subjects to study urinary drug and metabolite profiles. Rates of O-demethylation yielding the main metabolite dextrorphan were expressed by the urinary dextromethorphan/dextrorphan metabolic ratio. We found a bimodal distribution of this parameter in our population study, which indicates that there are two phenotypes for dextromethorphan O-demethylation. The antimode at a metabolic ratio of 0.3 separated the poor metabolizer (PM; n = 23; prevalence of 9%) from extensive metabolizer (EM) phenotypes. Urinary output of dextrorphan was less than 6% of the dose in all PMs and was 50% in the 245 EMs. Pedigree analysis of 14 family studies revealed an autosomal-recessive transmission of deficient dextromethorphan O-demethylation. In these families, 37 heterozygous genotypes could be identified; however, through use of the urinary drug and metabolite analysis it was not possible to identify the heterozygous genotypes within the EM phenotype group. Co-segregation of dextromethorphan O-demethylation with debrisoquin 4-hydroxylation was also studied. Complete concordance of the two phenotypic assignments was obtained, with a Spearman rank correlation coefficient of rs = 0.78 (n = 62; P less than 0.0001) for dextromethorphan and debrisoquin metabolic ratios. Presumably the two drug oxidation polymorphisms are under the same genetic control. Thus the innocuousness and ubiquitous availability of dextromethorphan render it attractive for worldwide pharmacogenetic investigations in man.

Inherited deficiency in mephenytoin hydroxylation was observed in a family study. It is important that the propositus was of the extensive metabolizer phenotype for the genetically controlled hydroxylation of debrisoquine. Thus, a genetic polymorphism of drug hydroxylation was suspected for mephenytoin. A population study of mephenytoin hydroxylation, combined with identification of extensive and poor debrisoquine hydroxylation phenotypes, was carried out in 221 unrelated normal volunteers. Twelve of them (5%) exhibited defective aromatic hydroxylation of mephenytoin, and 23 (10%) could be identified as poor metabolizers of debrisoquine. Amongst these 35 subjects with a drug hydroxylation deficiency, 3 (or 0.5%; 1 female, 2 males) displayed both defects simultaneously. A panel study of 10 extensive and 10 poor metabolizers of mephenytoin showed that the ability to perform aromatic hydroxylation of the demethylated mephenytoin metabolite nirvanol (5-phenyl-5-ethylhydantoin) was co-inherited with the mephenytoin hydroxylation polymorphism. Family studies suggested that poor metabolizer phenotypes of nirvanol and mephenytoin were most likely to have the homozygous genotype for an autosomal recessive allele of deficient aromatic drug hydroxylation. Intra-subject comparison of the debrisoquine and mephenytoin hydroxylation phenotypes in these subjects indicated that deficiency in the two drug hydroxylations occurred independently. Consequently, the co-inheritance of extensive and poor hydroxylation of mephenytoin and nirvanol, respectively, represents a new drug hydroxylation polymorphism in man.

No abstract

The psychotropic ␤-carboline alkaloids, showing high affinity for 5-hydroxytryptamine, dopamine, benzodiazepine, and imidazoline receptors and the stimulation of locus coeruleus neurons, are formed endogenously from tryptophan-derived indolealkylamines through the Pictet-Spengler condensation with aldehydes in both plants and mammals. Cytochromes P450 1A1 (18.5), 1A2 (20), and 2D6 (100) catalyzed the O-demethylation of harmaline, and CYP1A1 (98.5), CYP1A2 (35), CYP2C9 (16), CYP2C19 (30), and CYP2D6 (115) catalyzed that of harmine (relative activities). The dehydrogenation/aromatization of harmaline to harmine was not carried out by aromatase (CYP19), CYP1A2, CYP2C9, CYP2D6, CYP3A4, pooled recombinant cytochromes P450, or human liver microsomes (HLMs). Kinetic parameters were calculated for the O-demethylations mediated by each isozyme and by pooled HLMs. K cat (min Ϫ1 ) and K m (M) values for harmaline were: CYP1A1, 10. 8 and 11.8; CYP1A2, 12.3 and 13.3; CYP2C9, 5.3 and 175; CYP2C19, 10.3 and 160; and CYP2D6, 39.9 and 1.4. Values for harmine were: CYP1A1, 45.2 and 52.2; CYP1A2, 9.2 and 14.7; CYP2C9, 11.9 and 117; CYP2C19, 21.4 and 121; and CYP2D6, 29.7 and 7.4. Inhibition studies using monoclonal antibodies confirmed that CYP1A2 and CYP2D6 were the major isozymes contributing to both harmaline (20% and 50%, respectively) and harmine (20% and 30%) O-demethylations in pooled HLMs. The turnover numbers for CYP2D6 are among the highest ever reported for a CYP2D6 substrate. Finally, CYP2D6-transgenic mice were found to have increased harmaline and harmine O-demethylase activities as compared with wild-type mice. These findings suggest a role for polymorphic CYP2D6 in the pharmacology and toxicology of harmine and harmaline.The ␤-carboline alkaloids are present in plants and have been of interest due to their psychotropic properties (Picada et al., 1997). They may be formed endogenously from tryptophan-derived indolealkylamines through the Pictet-Spengler condensation with simple aldehydes or with pyruvic acid in mammals, including humans (Airaksinen and Kari, 1981;Melchior and Collins, 1982). Moreover, certain ␤-carbolines, such as pinoline, tryptoline, 6-hydroxy-tetrahydro-␤-carboline, harman, and norharman (Table 1), have been reported as normal constituents of human tissues and body fluids. Their levels in humans are usually elevated after drinking alcohol. The association of ␤-carbolines with alcohol dependence and brain damage has been suggested (Melchior and Collins, 1982;Collins, 2002).Endogenous and exogenous ␤-carboline alkaloids were reported to exert a wide spectrum of psychopharmacological and behavioral effects in the brain (Airaksinen and Kari, 1981). Most ␤-carbolines are strong reversible inhibitors of monoamine oxidase (MAO). Among them, harmaline and harmine (Table 1) exhibit the most potent inhibition toward purified MAO-A activity (Kim et al., 1997), and these are the principal active agents in Peganum harmala, a plant that has been used in traditional medicine for two millennia (Lamchou...