The genetic control of sparteine and debrisoquine metabolism in man with new methods of analysing bimodal distributions.

Abstract

SUMMARY Debrisoquine and sparteine tests were carried out in 215 random white British subjects. There is a high degree of correlation between the urinary 'metabolic ratios' of the two drugs. New A polymorphism has also been described for the metabolism of sparteine, an alkaloid which has been used as an anti-arrhythmic and oxytocic drug. One phenotype with a frequency of 0-05 in the German population was unable to metabolise the compound. The other phenotype produced two substances thought to result from N-oxidation. The limited amount of pedigree information previously available suggested that 'non-metabolisers' might be autosomal recessives, homozygous for an allele with a frequency of 0-22.23 This paper presents information to show (1) the manner of inheritance of sparteine metabolism, (2) the relationship between the genetic control of 4-hydroxylation of debrisoquine and the metabolism of sparteine, and (3) the use of improved methods for the analysis of bimodal (and trimodal) frequency distributions. MethodsThe debrisoquine phenotyping test' and the analytical procedure5 were carried out as previously described.Received for publication 10 September 1982. Accepted for publication 19 February 1983. The sparteine phenotyping test2 was carried out as follows. Subjects who had fasted overnight ingested a 100 mg capsule of sparteine sulphate. They remained in the fasting state for a further 2 hours thereafter and were then allowed normal food and drink. The urine excreted 11 to 13 hours after drug ingestion was collected for analysis. The analytical procedure3 was carried out as described previously. The areas of the gas liquid chromatography peaks for sparteine, 2-dehydrosparteine, and 5-dehydrosparteine were measured. The 'metabolic ratio' was calculated as: area of sparteine peak sum of areas of peaks of 2-dehydrosparteine and 5-dehydrosparteine. POPULATION SURVEY OF UNRELATED WHITE BRITISH SUBJECTSA total of 215 healthy unrelated adult subjects (who had given informed consent) were tested with both compounds, with intervals of at least 4 days being allowed between the two tests.The families studied whose members were tested with the two drugs were obtained by two methods of ascertainment. (1) Some of the families published in a previous report1 were studied because they contained a debrisoquine 'poor metaboliser', found in the population survey of unrelated white British adult subjects. (2) Other families were investigated because they contained a proband who was found in the present population sample of unrelated British 321 on 11 May 2018 by guest. Protected by copyright.

Polymorphism of debrisoquine hydroxylation among Finns and Lapps.

“…The metabolic ratio (MR) was calculated by dividing the % of debrisoquine excreted by the % of the 4-hydroxy metabolite excreted in urine. Poor metabolizers are usually assigned a MR > 12.6 (Evans et al, 1983).…”

Sparteine oxidation polymorphism: a family study.

“…However, assessment of sparteine oxidation based on the peak area MR cannot distinguish the two genotypes within the dominant phenotype (Eichelbaum et al, 1979;Evans et al, 1983). Combined family and population data have indicated that sparteine metabolism is impaired in heterozygotes compared with homozygous dominants (Evans et al, 1983 The aim of the present study was to examine the urinary excretion pattern of sparteine and dehydrosparteines in the three genotypes.…”

“…Thus, two phenotypes are clearly defined: poor metabolizers (PM), who are homozygous for a recessive allele, and an extensive metabolizer (EM) phenotype comprising both heterozygotes and homozygous dominants (Eichelbaum et al, 1979;Evans et al, 1983). Earlier studies demonstrated coregulation of sparteine and debrisoquine oxidation (Eichelbaum et al, 1982;Inaba et al, 1983) but conflicting data have recently appeared (Evans et al, 1983;Eichelbaum & Woolhouse, 1985).…”

“…Combined family and population data have indicated that sparteine metabolism is impaired in heterozygotes compared with homozygous dominants (Evans et al, 1983 The aim of the present study was to examine the urinary excretion pattern of sparteine and dehydrosparteines in the three genotypes. Therefore, siblings and parents of 20 unrelated PM probands volunteered to take a test dose of sparteine.…”

“…Thus, two phenotypes are clearly defined: poor metabolizers (PM), who are homozygous for a recessive allele, and an extensive metabolizer (EM) phenotype comprising both heterozygotes and homozygous dominants (Eichelbaum et al, 1979;Evans et al, 1983). Earlier studies demonstrated coregulation of sparteine and debrisoquine oxidation (Eichelbaum et al, 1982;Inaba et al, 1983) but conflicting data have recently appeared (Evans et al, 1983;Eichelbaum & Woolhouse, 1985). Poor metabolism of sparteine and debrisoquine is associated with poor hydroxylation of imipramine (Br0sen et al,in preparation) and likewise the oxidation of metoprolol (Lennard et al, 1982), nortriptyline (Mellstrom et al, 1981) and desipramine (Bertilsson & Aberg-Wisted, 1983) is impaired in poor metabolizers of debrisoquine.…”