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Clinical Pharmacology and Therapeutics Oct 1988The metabolic ratios (MRs) between debrisoquin and 4-hydroxydebrisoquin in urine after a single oral dose of 10 mg debrisoquin were bimodally distributed in 757 healthy,...
The metabolic ratios (MRs) between debrisoquin and 4-hydroxydebrisoquin in urine after a single oral dose of 10 mg debrisoquin were bimodally distributed in 757 healthy, white Swedish volunteers. Forty-one subjects (5.4%) had an MR greater than 12.6 and were classified as slow debrisoquin hydroxylators. The MR was reproducible in urine stored at +8 degrees C for 1 week and at -20 degrees C over a period of 5 years. Collection intervals of 6 or 12 hours gave the same MR. Intraindividual repeatability of the debrisoquin phenotyping test was established in 37 subjects examined twice at least 2 weeks apart. The calculated frequency of the single allele that is believed to control deficient debrisoquin hydroxylation is similar among white Swedish people, as among other white groups examined so far; however, it is significantly different from the frequency in certain Oriental groups. Detailed comparisons of the prevalence of slow debrisoquin hydroxylation in different ethnic groups are not possible due to shortcomings in current epidemiologic techniques used (small materials, the location of the antimode distinguishing rapid and slow hydroxylators unknown, and family studies missing).
Topics: Adolescent; Adult; Aged; Debrisoquin; Female; Genotype; Humans; Hydroxylation; Isoquinolines; Male; Middle Aged; Polymorphism, Genetic; Sweden
PubMed: 3168394
DOI: 10.1038/clpt.1988.176 -
Clinical Pharmacology and Therapeutics Jul 1988The capacity for debrisoquin metabolism was determined in 377 healthy Spanish volunteers by measuring the amount of debrisoquin and its main metabolite,... (Comparative Study)
Comparative Study
The capacity for debrisoquin metabolism was determined in 377 healthy Spanish volunteers by measuring the amount of debrisoquin and its main metabolite, 4-hydroxydebrisoquin, in urine after an oral dose of debrisoquin. Debrisoquin oxidation was polymorphic, with 25 subjects (6.6%) phenotyped as poor metabolizers whereas 352 subjects (93.4%) were classified as extensive metabolizers. The metabolic ratio between debrisoquin and 4-hydroxydebrisoquin (percent of dose) in 6-hour urine samples ranged from 0.03 in extensive metabolizers to 93.5 in poor metabolizers. The proportion of poor metabolizers found is in the range observed in other white populations studied.
Topics: Adolescent; Adult; Cytochrome P-450 Enzyme System; Debrisoquin; Female; Humans; Isoenzymes; Isoquinolines; Male; Middle Aged; Oxidation-Reduction; Phenotype; Spain
PubMed: 3391005
DOI: 10.1038/clpt.1988.115 -
Clinical Pharmacology and Therapeutics Nov 1979The alicyclic and aromatic hydroxylation of debrisoquin was studied in Ghanaians. As in a previously studied Caucasian population, the alicyclic 4-hydroxylation of... (Comparative Study)
Comparative Study
The alicyclic and aromatic hydroxylation of debrisoquin was studied in Ghanaians. As in a previously studied Caucasian population, the alicyclic 4-hydroxylation of debrisoquin in Ghanaians was polymorphic. Three phenotypes were observed: homozygous extensive metabolizers (58%), heterozygous extensive metabolizers (36%), and homozygous poor metabolizers (6%). In contrast, British Caucasians are primarily monomorphic extensive metabolizers (92%) and homozygous poor metabolizers comprise 8% of the population. Urinary recovery of the drug and its hydroxylated metabolites was significantly less in the Ghanaian subjects. In both Ghanaian and British populations, aromatic hydroxylation producing 5-, 6-, 7-, and 8-hydroxydebrisoquin was shown to parallel the alicyclic 4-hydroxylation of debrisoquin, and thus to be controlled by the same gene locus. Debrisoquin is advocated as a tool for uncovering polymorphism in drug oxidation and its interethnic variations.
Topics: Adult; Black People; Debrisoquin; Female; Ghana; Heterozygote; Homozygote; Humans; Hydroxylation; Isoquinolines; Male; Middle Aged; Phenotype; Polymorphism, Genetic; White People
PubMed: 498701
DOI: 10.1002/cpt1979265584 -
Clinical Pharmacology and Therapeutics Apr 1986Eleven healthy nonsmokers with wide variation in the ability to hydroxylate debrisoquin (D) were given single oral doses of amitriptyline and nortriptyline on different...
Eleven healthy nonsmokers with wide variation in the ability to hydroxylate debrisoquin (D) were given single oral doses of amitriptyline and nortriptyline on different occasions. The urinary D/4-hydroxy-D ratio correlated significantly (P less than 0.01) with all three parameters of amitriptyline disposition measured (total plasma clearance, clearance by demethylation, and clearance by pathways other than demethylation), with rs = -0.89, -0.78, and -0.83, respectively. In contrast, we failed to demonstrate such correlations in a previous sample of smokers. Our data suggest that there may be a common regulation of the hydroxylation of D and the oxidative metabolism of amitriptyline in nonsmokers. It is hypothesized that an additional demethylase/hydroxylase is induced in smokers that is not involved in D hydroxylation.
Topics: Administration, Oral; Adult; Amitriptyline; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2D6; Debrisoquin; Female; Gas Chromatography-Mass Spectrometry; Humans; Hydroxylation; Kinetics; Male; Metabolic Clearance Rate; Middle Aged; Mixed Function Oxygenases; Nortriptyline; Phenotype
PubMed: 3956053
DOI: 10.1038/clpt.1986.56 -
Clinical Pharmacology and Therapeutics May 1985The ability to oxidize sparteine to form 2- and 5-dehydrosparteine was studied in 154 healthy Ghanaians. Although the urinary metabolic sparteine/dehydrosparteines ratio... (Comparative Study)
Comparative Study
The ability to oxidize sparteine to form 2- and 5-dehydrosparteine was studied in 154 healthy Ghanaians. Although the urinary metabolic sparteine/dehydrosparteines ratio varied widely (from 0.14 to 12.5), in contrast to observations in several Caucasian population groups the ratios were not bimodally distributed and no phenotypically poor oxidizers of sparteine were found. The ability of these same subjects to oxidize debrisoquin and phenformin was also studied in 141 and 143 subjects. Of the 141 subjects dosed with debrisoquin, 10 proved to be poor oxidizers, and of the 143 subjects dosed with phenformin, 11 were poor oxidizers. All the poor oxidizers of debrisoquin were also poor oxidizers of phenformin. The 10 confirmed poor metabolizers of debrisoquin, who had debrisoquin metabolic ratios ranging from 14.4 to 52.0, had sparteine metabolic ratios ranging only from 0.15 to 12.5. Whereas Caucasian poor metabolizers of sparteine excrete less than 2.0% of a dose as dehydrosparteines, the mean excretion of dehydrosparteines in our 10 subjects was 20.6% +/- 13.2%. The overall rank correlation between the sparteine and debrisoquin metabolic ratios was low (rs = 0.47), while the coefficient of determination for linear regression (r2) was only 0.17. Our data show that the ability of Ghanaians to oxidize sparteine is largely independent of their capacity for debrisoquin oxidation and is indicative of a major interethnic difference in the genetic control of these reactions.
Topics: Administration, Oral; Adolescent; Adult; Debrisoquin; Female; Ghana; Humans; Isoquinolines; Kinetics; Male; Middle Aged; Phenformin; Phenotype; Sparteine; White People
PubMed: 3987174
DOI: 10.1038/clpt.1985.81 -
Pharmacogenomics Nov 2021Genetic variation in the gene encoding CYP2D6 is used to guide drug prescribing in clinical practice. However, genetic variants in CYP2D6 show substrate-specific effects...
Genetic variation in the gene encoding CYP2D6 is used to guide drug prescribing in clinical practice. However, genetic variants in CYP2D6 show substrate-specific effects that are currently not accounted for. With a systematic literature, we retrieved 22 original studies describing experiments focusing on alleles (*1, *2, *10 and *17) and substrates. Allele activity (clearance of the allele of interest divided by the clearance of the wildtype) was extracted. The results support the hypothesis of the existence of substrate specificity of the *17-allele (higher debrisoquine clearance), a subtle effect of the *10-allele (lower dextromethorphan clearance) but no substrate-specific effect of the *2-allele. Although our results support substrate specificity, for most substrates data are too sparse and require further studies.
Topics: Alleles; Cytochrome P-450 CYP2D6; Debrisoquin; Genetic Variation; Humans; Isoenzymes; Substrate Specificity
PubMed: 34569808
DOI: 10.2217/pgs-2021-0093 -
Clinical Pharmacology and Therapeutics May 1989Mephenytoin (100 mg) and debrisoquin (10 mg) were administered orally, both separately and together, to 41 healthy subjects. The ratios between the S and R enantiomers...
Mephenytoin (100 mg) and debrisoquin (10 mg) were administered orally, both separately and together, to 41 healthy subjects. The ratios between the S and R enantiomers of mephenytoin and between debrisoquin and 4-OH-debrisoquin in urine were determined by use of GC. These ratios were used as measures of drug hydroxylation. There was no change in the phenotypic trait values of the two drugs when they were coadministered. Mephenytoin and debrisoquin then were coadministered to 253 healthy Swedish subjects, before bedtime, and urine samples were collected at periods of 0 to 8, 8 to 24, and 24 to 32 hours after drug administration. In the first sample, seven of the 253 subjects (2.8%, 95% confidence interval 0.8% to 4.8%) had an S/R ratio of greater than 0.8; this indicated that they were poor hydroxylators of S-mephenytoin. In the two consecutive samples, the S/R ratios of mephenytoin did not change in these seven persons, whereas it decreased to less than 0.2 in the third sample in the extensive hydroxylators. As was reported before, there was no relationship between the mephenytoin S/R ratio and the debrisoquin metabolic ratio (rs = 0.01). Coadministration of debrisoquin and mephenytoin before bedtime and urine collection during two consecutive nights allow for an accurate determination of both phenotypes in the population.
Topics: Adolescent; Adult; Aged; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C19; Cytochrome P-450 Enzyme System; Debrisoquin; Drug Interactions; Female; Humans; Hydantoins; Hydroxylation; Isoquinolines; Male; Mephenytoin; Middle Aged; Mixed Function Oxygenases; Phenotype; Sweden
PubMed: 2721104
DOI: 10.1038/clpt.1989.63 -
Clinical Pharmacology and Therapeutics Oct 1985Interethnic differences in debrisoquin and mephenytoin hydroxylation have been compared between normal white (n = 183) and Japanese (n = 100) subjects with the 8-hour... (Comparative Study)
Comparative Study
Interethnic differences in debrisoquin and mephenytoin hydroxylation have been compared between normal white (n = 183) and Japanese (n = 100) subjects with the 8-hour urinary metabolic ratio of debrisoquin and the urinary S/R enantiomeric ratio of mephenytoin to identify extensive (EM) and poor (PM) metabolizers. In white subjects the frequency of PMs was 8.7% and 2.7% for debrisoquin and mephenytoin, respectively. In contrast, in Japanese subjects no PMs of debrisoquin were identified, while the incidence of PMs of mephenytoin was 18%. These substantial differences (P less than 0.001) in polymorphic distributions of oxidative drug metabolizing ability have implications for interethnic efficacy and toxicity of drugs and other xenobiotics that are metabolized by the involved cytochrome P-450 isozymes.
Topics: Administration, Oral; Adolescent; Adult; Debrisoquin; Female; Genotype; Humans; Hydantoins; Hydroxylation; Isoquinolines; Japan; Male; Mephenytoin; Middle Aged; Phenotype; Random Allocation; White People
PubMed: 4042523
DOI: 10.1038/clpt.1985.194 -
Lancet (London, England) Feb 1991
Topics: Alleles; DNA; Debrisoquin; Humans; Mutation; Phenotype; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Probability
PubMed: 1671255
DOI: 10.1016/0140-6736(91)90991-w -
Clinical Pharmacology and Therapeutics Jul 1989The pharmacokinetics of a single oral dose of 6 mg perphenazine was studied in a group of six slow and six rapid hydroxylators of debrisoquin. Peak serum concentrations...
The pharmacokinetics of a single oral dose of 6 mg perphenazine was studied in a group of six slow and six rapid hydroxylators of debrisoquin. Peak serum concentrations of perphenazine were significantly higher in slow hydroxylators than they were in rapid hydroxylators (2.4 +/- 0.6 versus 0.7 +/- 0.3 nmol/L, p less than 0.001). The AUC(0-12) was also higher in slow hydroxylators than it was in rapid hydroxylators (18.5 +/- 6.2 versus 4.5 +/- 2.5 nmol.L-1.hr, p less than 0.001). The data suggest that the disposition of the antipsychotic drug perphenazine covaries with polymorphic debrisoquin hydroxylation.
Topics: Administration, Oral; Adult; Debrisoquin; Female; Humans; Hydroxylation; Isoquinolines; Male; Perphenazine; Polymorphism, Genetic
PubMed: 2743709
DOI: 10.1038/clpt.1989.109