Salivary analysis for determination of dextromethorphan metabolic phenotype.

Debrisoquin oxidative phenotype is a determinant of pharmacologic response for many drugs. Poor and extensive metabolizers can be identified by the dextromethorphan metabolic ratio (dextromethorphan/dextrorphan). We developed and tested a method to determine debrisoquin phenotype on the basis of the metabolic ratio in saliva. Each of 62 normal volunteers was given a 50 mg capsule of dextromethorphan hydrobromide and collected urine (0 to 8 hours) and saliva (at 3 hours). Dextromethorphan and dextrorphan in saliva and urine were assayed by HPLC. The distributions of paired urinary and 3-hour salivary metabolic ratios of samples from 61 subjects were compared. The urinary and salivary metabolic ratios were distributed trimodally and bimodally, respectively. The Spearman rank correlation coefficient for logarithm of urinary metabolic ratio vs that of salivary metabolic ratio was 0.704. All the poor metabolizers identified by urinary metabolic ratio were also identified by the metabolic ratio in saliva at 3 hours (100% concordance). This study demonstrates that salivary analysis for determination of dextromethorphan metabolic phenotype is feasible.

Determination of dextromethorphan metabolic phenotype by salivary analysis with a reference to genotype in Chinese patients receiving renal hemodialysis.

BACKGROUND: The polymorphic metabolism of debrisoquin and sparteine by cytochrome P450IID6 (CYP2D6) is genetically determined. Determination of the CYP2D6 metabolic phenotype with conventional urine analytic methods is not feasible in anuric patients with renal failure. The possibility of using salivary analysis, with dextromethorphan as a probe drug, to determine the CYP2D6 metabolic phenotype in patients with renal failure was evaluated. METHODS AND RESULTS: One hundred four Chinese patients with renal failure were recruited. All 104 patients were receiving hemodialysis. Saliva was collected before and at 3 hours after each patient took a capsule of dextromethorphan hydrobromide (30 mg). Four patients were excluded because of insufficient samples of saliva. The distribution of logarithms of the metabolic ratios (log[MR]) in the 100 patients appeared to be normal. Administration of quinidine sulfate (200 mg twice daily) to nine of the patients significantly and markedly increased the dextromethorphan metabolic ratios. The metabolic ratios of nine patients pretreated with quinidine were higher than any of the 100 patients with renal failure who did not receive quinidine pretreatment. A metabolic ratio of 33 separated these two groups. Genomic deoxyribonucleic acid was extracted from whole blood in a subset of patients. Polymerase chain reaction (PCR)-based methods were used to detect the CYP2D6 and B mutant genes. Mutant B alleles (which are common in white poor metabolizers) of CYP2D6 genes were not detected in any of the 47 subjects tested. A PCR-based test of cytosine (C188) to thymine (T188) polymorphism at 188 base pairs in exon 1 of CYP2D6 genes was performed in 61 patients. Subjects who were homozygous for C188 had significantly (p = 0.0067) lower log[MR] values than those who were homozygous for T188. CONCLUSIONS: Determination of dextromethorphan metabolic ratios in saliva is feasible in patients with renal failure requiring hemodialysis. All subjects in this study appeared to be "extensive metabolizer" phenotype for CYP2D6, and no poor metabolizer was identified. From the results with quinidine pretreatment, a metabolic ratio of 33 is suggested to be a tentative antimode for identification of poor metabolizers in patients with renal failure.

Snuff dipping and oral cancer among women in the southern United States.

A case-control study in North Carolina involving 255 women with oral and pharyngeal cancer and 502 controls revealed that the exceptionally high mortality from this cancer among white women in the South is primarily related to chronic use of snuff. The relative risk associated with snuff dipping among white nonsmokers was 4.2 (95 per cent confidence limits, 2.6 to 6.7), and among chronic users the risk approached 50-fold for cancers of the gum and buccal mucosa--tissues that come in direct contact with the tobacco powder. In the absence of snuff dipping, oral and pharyngeal cancer resulted mainly from the combined effects of cigarette smoking and alcohol consumption. The carcinogenic hazard of oral snuff is of special concern in view of the recent upswing in consumption of smokeless tobacco in the United States.