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At least 19 recordsLinked to original sources
PubMed1997

Quantification of the O- and N-demethylated and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid, and poor debrisoquine hydroxylators.

The O-demethylation of codeine is polymorphic and catalyzed by CYP2D6. The metabolites of codeine formed through O- and N-demethylation as well as glucuronidation were quantified in the ultrarapid metabolizers of debrisoquine and compared with the normal extensive (EM) and poor metabolizers (PM). The urinary codeine and its seven metabolites were detected after 25 mg codeine in 24 healthy Caucasian subjects with low debrisoquine metabolic ratios (MR, < or = 0.11) and a group of 132 subjects tested earlier with codeine and debrisoquine including 114 EMs (MR < 12.6) and 18 PMs (MR > 12.6). Whereas the O-demethylated metabolites accounted for < 0.4% of the total recovery on average in the PMs and 1.7% to 8.7% in the EMs, they accounted for 15.3% in the 24 subjects with ultrarapid metabolism of debrisoquine. This study suggests that the ultrarapid debrisoquine hydroxylators may develop increased O-demethylated metabolite-dependent effects or side-effects of codeine.

Adolescent↗
PubMed2005

Determination of debrisoquine and 4-hydroxydebrisoquine by high-performance liquid chromatography: application to the evaluation of CYP2D6 genotype and debrisoquine metabolic ratio relationship.

The drug-metabolizing cytochrome P450 (CYP) enzyme CYP2D6 is involved in the metabolism of several clinically important drugs. So far more than 50 different CYP2D6 allelic variants have been described, and thus there is an increased need for routine high-performance liquid chromatography (HPLC) methods for the evaluation of the functional implication of CYP2D6 polymorphism. Debrisoquine is metabolized to 4-hydroxydebrisoquine by CYP2D6, and therefore it has been used widely to determine the hydroxylation capacity of the enzyme. The aim of the present study was to develop a simple, accurate HPLC method with ultraviolet detection for the measurement of debrisoquine and 4-hydroxydebrisoquine in urine for evaluation of the relationship between CYP2D6 enzyme activity and genotypes. For the HPLC determination, a C18 extraction column was used with a flow rate of 0.8 mL/min and detection at 210 nm. The compounds were eluted from the column in less than 10 min. Coefficients of variation at all concentrations were less than 4% for both compounds. The debrisoquine/4-hydroxydebrisoquine ratio (debrisoquine metabolic ratio) was determined in a panel of 16 Caucasian healthy volunteers with zero (poor metabolizers), one, two or more than two (ultrarapid metabolizers) CYP2D6 active genes. Significant correlation (p<0.05) between the number of CYP2D6 active genes and the hydroxylation capacity of the enzyme was found. The present HPLC method was simple, fast and accurate, and thus will be useful for the evaluation of CYP2D6 hydroxylation capacity in pharmacogenetic studies.

Adolescent↗
PubMedDate not supplied

Inhibition of debrisoquin clearance in perfused rat livers and inhibition of dextromethorphan metabolism in human liver microsomes by 4-hydroxydebrisoquin or other metabolites of debrisoquin.

Debrisoquin undergoes oxidative metabolism to 4-hydroxydebrisoquin, catalyzed by cytochrome CYP2D1 in rats and CYP2D6 in humans. Cytochrome CYP2D6 also plays a major role in dextromethorphan O-demethylation. In preliminary studies in perfused Lewis rat livers, we observed a difference in repeat clearance experiments using debrisoquin, but not dextromethorphan. To determine whether this change in clearance with time was due to the accumulation of 4-hydroxydebrisoquin, we sequentially used a recirculating and nonrecirculating perfusion system in the same liver perfusion experiment. We also studied the kinetics of dextromethorphan O-demethylation in microsomes prepared from human and rat livers in the presence and absence of 4-hydroxydebrisoquin. Results from the perfused rat liver experiments showed a drop in clearance from 3.27 +/- 0.57 ml/min (clearance 1) to 1.61 +/- 0.27 ml/min (clearance 2) (p less than 0.05 vs. clearance 1) during recirculation, but clearance returned to 3.21 +/- 0.46 ml/min (clearance 3, no significance vs. clearance 1) after a 30-min period of liver perfusion using a nonrecirculating system. There was significant accumulation of 4-hydroxydebrisoquin in the liver perfusate during recirculation, and concentrations fell when the nonrecirculating system was used. In microsomal studies, 4-hydroxydebrisoquin competitively inhibited dextromethorphan metabolism in human microsomes was 600 microM. These data suggest that: (a) 4-hydroxydebrisoquin and/or other metabolites of debrisoquin have an inhibitory effect on CYP2D1 and CYP2D6; (b) the active site of human CYP2D6 has different substrate specificity than the rat isozyme (CYP2D1) and/or that the pathways of metabolism of dextromethorphan are different in the Lewis rat and not primarily dependent on the activity of CYP2D1.

Animals↗
PubMed1989

Plasma debrisoquin levels in the assessment of reduction of plasma homovanillic acid. The debrisoquin method.

Plasma concentrations of unconjugated homovanillic acid (pHVA) reflect both central nervous system (CNS) and peripheral dopamine metabolism. Debrisoquin sulfate (DBQ) blocks peripheral, but not CNS, production of HVA from dopamine. Administration of DBQ has been used to decrease the proportion of peripherally produced HVA in pHVA measurements, making such measurements more reflective of CNS turnover of dopamine. We studied the relationships between DBQ dose, plasma DBQ (pDBQ) levels, and changes in pHVA in a group of 21 subjects (9 normal controls and 12 with Tourette's syndrome). DBQ dose was moderately correlated with pDBQ levels (r = 0.63, p = 0.002). Subjects (n = 8) with mean pDBQ levels above 60 ng/ml had a 48% to 66% decrease in mean pHVA levels; this may reflect nearly complete inhibition of peripheral HVA production. Subjects (n = 13) with mean pDBQ levels below 55 ng/ml had decreases in pHVA levels from 10% to 58%. No debrisoquin was detected in cerebrospinal fluid samples. These data suggest that pDBQ levels above 60 ng/ml are sufficient to assure substantial inhibition of peripheral HVA production and that monitoring pDBQ levels may be useful when employing this method for studying CNS metabolism.

Adult↗
PubMed1992

The debrisoquine metabolic phenotype and DNA-based assays: implications of misclassification for the association of lung cancer and the debrisoquine metabolic phenotype.

Debrisoquine is an antihypertensive drug that is metabolized by cytochrome P4502D6. Deficient metabolism is inherited as an autosomal recessive condition. We previously reported in a case-control study that extensive metabolizers of debrisoquine were at greater risk of lung cancer compared to poor and intermediate metabolizers. Cloning of the gene that encodes P4502D6 (CYP2D6) led to the identification of both wild-type and mutant forms of the gene. Subsequently, a DNA-restriction fragment length polymorphism (RFLP) was identified, and a Southern hybridization-based test was developed in an attempt to define the genotype. When the DNA-RFLP test was applied to stored DNA from our study subjects there was neither a significant association with the metabolic phenotype nor an association with lung cancer. Further work has demonstrated that the wild-type gene, which was characterized by a 29-kb allele, can also contain mutations that result in nonfunctional or absent proteins. When these mutations are present, individuals exhibit the poor or intermediate metabolizer phenotype in spite of the presence of the 29-kb putative wild-type allele. Sequence determination of the mutants led to the development of techniques to exploit the polymerase chain reaction, which, together with Southern analysis, have been reported to detect as many as 95% of poor metabolizers. This technique is being used to examine the association of the extensive metabolizer genotype with lung cancer in the subjects from the case-control study. Preliminary results indicate a weak association between the homozygous wild-type genotype and lung cancer; in contrast, the extensive metabolizer phenotype is strongly associated with lung cancer in this subset.(ABSTRACT TRUNCATED AT 250 WORDS)

Case-Control Studies↗
PubMed1997

Characterization of stereoselectivity and genetic polymorphism of the debrisoquine hydroxylation in man via analysis of urinary debrisoquine and 4-hydroxydebrisoquine by capillary electrophoresis.

Using capillary zone electrophoresis with a phosphate buffer at pH 2.5 containing 50 mM heptakis-(2,3,6-tri-O-methyl)-beta-CD as chiral selector, the separation of the enantiomers of the main metabolite of debrisoquine (DEB), 4-hydroxydebrisoquine (4-OHDEB), is reported. For extraction of underivatized urinary DEB, S-4-OHDEB and R-4-OHDEB, a procedure using disposable cartridges containing a polystyrene-based polymer was developed. A few nL of the extracts were analyzed in a 60 cm fused-silica capillary of 50 microns ID and solute detection was effected at 195 nm. For all three compounds, a mean (n = 5) recovery of about 73% and a detection limit of about 150 ng/mL were noted. Data obtained with urines that were received for routine phenotyping with DEB and mephenytoin confirmed the almost exclusive formation of S-4-OHDEB. Under the described conditions, no R-4-OHDEB could be detected. With these data and those obtained employing no chiral selector in the buffer, differentiation between extensive metabolizer phenotypes (EM) and poor metabolizer phenotypes (PM) for DEB was unambiguously possible by the presence of a significant peak and no (or minor) peak for 4-OHDEB, respectively. Data obtained for ten EM subjects and five PM subjects were found to agree with those generated by the routine assay based on gas chromatography. The capillary electrophoretic assays described are simple, reproducible (relative standard deviation of peak area ratios < 3%), require no sample derivatization, consume no halogenated organic solvents, and operate with inexpensive separation columns as well as small amounts of chemicals.

Debrisoquin↗
PubMed1986

Oxidation of tricyclic antidepressant drugs, debrisoquine and 7-ethoxyresorufin, by human liver preparations.

Data obtained from human studies in vivo show that the dispositions of the tricyclic antidepressant drugs desmethylimipramine (DMI) and nortriptyline are related to the debrisoquine hydroxylation phenotype. To obtain insight into the enzymic mechanisms behind this, the metabolism of debrisoquine and antidepressant drugs by human liver preparations have been studied. The 2-hydroxylation of DMI in vitro correlates with the 4-hydroxylation of debrisoquine among various livers (rs = 0.90). Debrisoquine inhibits DMI hydroxylation competitively, and DMI inhibits debrisoquine hydroxylation, suggesting that DMI hydroxylation is catalysed by the debrisoquine hydroxylase in human liver. By monitoring the hydroxylation of DMI in various fractions during separation and purification of cytochrome P-450 from human liver microsomes we have purified a cytochrome P-450 which efficiently hydroxylates this drug. The apparently electrophoretically homogeneous enzyme had a molecular weight of 51,500 and hydroxylated DMI and debrisoquine at rates of up to 0.95 and 0.45 nmol/min . nmol P-450, respectively. This is probably the major debrisoquine hydroxylating cytochrome P-450 in man. Nortriptyline 10-hydroxylation correlates strongly (r = 0.96) with debrisoquine hydroxylation in human liver microsomes. Nortriptyline inhibits DMI-hydroxylation competitively, and the drug also inhibits the 4-hydroxylation of debrisoquine. Thus it is probable that nortriptyline is hydroxylated by debrisoquine hydroxylase. Imipramine N-demethylation did not correlate significantly (P greater than 0.1) with debrisoquine hydroxylation among microsomes from nine livers. However, if a liver from a subject, which was a poor metabolizer of debrisoquine in vivo, was included, a correlation was obtained (r = 0.79, P less than 0.01, N = 10). Imipramine demethylation also correlated with DMI-hydroxylation only if the 'poor metabolizer' liver was included (r = 0.75, P less than 0.05, N = 10). Debrisoquine inhibited imipramine demethylation competitively. The data indicate that imipramine can interact with debrisoquine- and DMI-hydroxylase, but it is uncertain if this enzyme plays an important quantitative role in its demethylation. Ethoxyresorufin O-deethylation correlated with DMI hydroxylation (r = 0.80) in human liver preparations, and DMI inhibited the former reaction in what is probably a mixed competitive-non-competitive inhibition. Liver preparations from a subject who was a poor oxidizer of debrisoquine both in vivo and in vitro had unusually low capacity to metabolize ethoxyresorufin. Thus ethoxyresorufin, at least partly, seems to interact with an enzyme that can metabolize DMI in human liver.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

Effect of levomepromazine and metabolites on debrisoquine hydroxylation in the rat.

The influence of the major metabolites of the phenothiazine derivative, levomepromazine (methotrimeprazine), on hydroxylation of debrisoquine was examined in male Sprague-Dawley rats. The metabolic ratio of debrisoquine/4-hydroxy debrisoquine was first determined in rats after oral administration of 10 mg/kg of debrisoquine. Then the same dose of debrisoquine was co-administered with various doses of levomepromazine or one of its metabolites. Levomepromazine and its sulphoxidated, N-demethylated and O-demethylated metabolites caused highly significant and dose-dependent increases in the debrisoquine metabolic ratio. 3-Hydroxy levomepromazine had no significant effect on the metabolism of debrisoquine. This indicates that the non-hydroxylated metabolites of levomepromazine have relatively high affinities for the cytochrome P450 enzyme which converts debrisoquine to 4-hydroxy debrisoquine in the rat. Such metabolites may therefore be responsible for a considerable part of the inhibitory effect of debrisoquine hydroxylation previously reported in patients treated with phenothiazine neuroleptics.

Administration, Oral↗
PubMed1984

Relationship between oxidative metabolism of 2-acetylaminofluorene, debrisoquine, bufuralol, and aldrin in human liver microsomes.

The capacity of human liver microsomes from 28 individuals to metabolize debrisoquine and bufuralol, two drugs oxidized polymorphically in humans, as well as the carcinogen 2-acetylaminofluorene (AAF), was determined. In addition, the cytochrome P-450 content and the capacity of these microsomes to carry out the epoxidation of aldrin were measured. Interindividual differences in debrisoquine 4-hydroxylation, bufuralol 1-hydroxylation, and aldrin epoxidation were 12-, 20-, and 2.4-fold, respectively. The metabolism of debrisoquine was not correlated with cytochrome P-450 content (r = 0.26), whereas both the metabolism of bufuralol (r = 0.45; r2 = 0.20) and the epoxidation of aldrin (r = 0.72; r2 = 0.52) were correlated. Rates of debrisoquine and bufuralol metabolism were significantly correlated (r = 0.73), whereas only weak correlations existed between debrisoquine:aldrin (r = 0.49) and bufuralol:aldrin (r = 0.51). Because biphasic kinetics have been observed in human liver microsomes for the 7- and 5-hydroxylation of AAF, two concentrations of this substrate were used. The disappearance of AAF at either 0.37 or 50 microM was not correlated with debrisoquine, bufuralol, or aldrin metabolism. Similarly, at 0.37 microM AAF, no correlation existed between the formation of N-, 1-, 3-, 5-, 7-, and 9-hydroxylation products of AAF and debrisoquine, bufuralol, or aldrin metabolism. At 50 microM AAF, only the 7-hydroxylation of this substrate correlated with bufuralol metabolism (r = 0.47). This lack of, or weak correlation between pathways leading to metabolic activation (N-hydroxylation) or detoxication (C-hydroxylation) of the carcinogen AAF and debrisoquine, bufuralol, and aldrin metabolism strongly suggests that different forms of cytochrome P-450 are involved in these pathways. In contrast, exceptionally high correlations (r greater than 0.94) existed between N-OH-AAF:1-OH-AAF. N-OH-AAF:7-OH-AAF, and 7-OH-AAF:1-OH-AAF at the low concentration of AAF, and imply that similar forms of cytochrome P-450 produce these metabolites. However, at 50 microM AAF, these correlations are considerably weaker and explain less than 35% of the variance in the data. It is concluded, based on these multiple cross-correlations, that common cytochrome P-450 isoenzymes are involved in the formation of AAF metabolites, while the metabolism of debrisoquine, bufuralol, and aldrin is unrelated to the metabolism of this carcinogen in human liver microsomes.

2-Acetylaminofluorene↗
PubMedDate not supplied

Debrisoquine metabolism and lung cancer risk.

Previous reports of the association between the debrisoquine metabolic polymorphism and lung cancer risk have been conflicting. We examined the hypothesis that the genetically determined ability to metabolize debrisoquine identifies individuals at increased risk for lung cancer in a study designed to address some of the methodological criticisms of previous studies. A case-control study of 335 incident Caucasian lung cancer patients and 373 controls matched for age, race, sex, and hospital, was conducted at the National Naval Medical Center (Bethesda, MD) and at the Laval Hospital (Sainte-Foy, Quebec, Canada). Debrisoquine metabolic phenotype was determined by debrisoquine administration and analysis of debrisoquine and 4-hydroxydebrisoquine in the subsequent 8-h urine collected. Stratified and logistic regression analyses were used to evaluate the association between extensive or intermediate debrisoquine metabolism and lung cancer risk. We found no increased risk among extensive or intermediate metabolizers (odds ratio, 0.6; 95% confidence interval, 0.3-1.2). The lack of an association was not confounded by control diagnoses, medications used within 1 month of debrisoquine administration, smoking, stage, or histology of lung cancer. No relationship was found among either heavy smokers or light and nonsmokers. Our results do not support the role of debrisoquine metabolism as a marker for lung cancer risk. While the concept that polymorphisms of metabolism may account for differential susceptibility to lung cancer is sound, debrisoquine metabolic phenotype was not associated with lung cancer risk in these data.

Aged↗
PubMed1988

Dopamine metabolism and disposition in schizophrenic patients. Studies using debrisoquin.

Debrisoquin sulfate, a monoamine oxidase inhibitor that does not enter the brain, was administered to 23 schizophrenic subjects. Plasma, cerebrospinal fluid (CSF), and urine samples were obtained before and during debrisoquin administration and were assayed for their content of norepinephrine and dopamine metabolites, ie, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and dihydroxyphenylacetic acid. The severity of the patient's schizophrenic symptoms was also assessed with several types of rating scales. During debrisoquin administration there were significant reductions in plasma, urine, and CSF MHPG levels. Regression analyses suggested that the reduction in CSF MHPG level was probably due to the reduction in plasma MHPG level, which contributes to the CSF MHPG pool. Debrisoquin administration was not associated with changes in CSF HVA level, although it did produce marked reductions in plasma and urinary HVA and dihydroxyphenylacetic acid levels. Significant correlations between plasma and CSF concentrations of HVA were noted during, but not before, debrisoquin administration. Before debrisoquin administration there were trends toward positive relationships between symptom severity and plasma HVA concentrations, which became stronger and statistically significant during debrisoquin administration. These data suggest that debrisoquin may be used as a research tool to create a condition in which measures of HVA in peripheral body fluids reflect dopamine system function and metabolism within the central nervous system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Cytochrome P-450IID6 phenotyping in cancer patients: debrisoquin and dextromethorphan as probes.

The usefulness of substituting dextromethorphan for debrisoquin as a probe for cytochrome P-450IID6 deficiency was investigated in 20 male cancer patients. Each patient was studied on two occasions. An oral dose of dextromethorphan (60 mg) was administered to 13 patients and are week later an oral dose of debrisoquin (10 mg) was administered to each patient. The order was reversed for the other 7 patients. An 8-h urine sample was collected after administration of each test drug and assayed for parent drug and metabolites. Five poor metabolizers (PMs) and 15 extensive metabolizers (EMs) of debrisoquin were tested. The debrisoquin metabolic ratio (DMR), calculated as [parent drug]/[metabolite], correlated with the metabolic ratio of dextromethorphan (R2 = 0.58, P = 0.0001). All PMs of debrisoquin (metabolic ratio > 12.0) were easily identified as being PMs of dextromethorphan (metabolic ratio > 0.30). Within the EM group, there was a significant correlation between the metabolic ratios of debrisoquin and dextromethorphan (R2 = 0.82, P < 0.0001). There was not as clear a correlation in the PM group (R2 = 0.32, P = 0.32). These findings suggest that dextromethorphan can be substituted for debrisoquin in establishing the debrisoquin phenotype in a patient population with metastatic cancer.

Aged↗
PubMed1989

Multiple pathways of propranolol's metabolism are inhibited by debrisoquin.

We investigated the effect of debrisoquin on propranolol metabolism in six normal subjects who were extensive metabolizers of debrisoquin. Each subject was studied on two occasions. On the first occasion, each subject received oral propranolol (80 mg) alone; on the second occasion, 7 days later, each subject received a dose of propranolol (80 mg) 30 minutes after the administration of oral debrisoquin (40 mg). Oral propranolol clearance was reduced 33% +/- 16% (p less than 0.05) by the administration of debrisoquin. As predicted, the 4-hydroxypropranolol partial metabolic clearance was significantly (p less than 0.05) inhibited by debrisoquin. However, the side-chain oxidation pathway, as measured by naphthoxylactic acid, was also significantly (p less than 0.05) inhibited by debrisoquin. Debrisoquin administration did not change the renal clearance of any of the metabolites. These data support the usefulness of the in vivo inhibition model in the prediction of cosegregation of routes of metabolism. However, for propranolol, pathways of its metabolism that are not thought to cosegregate with debrisoquin was also inhibited.

Absorption↗
PubMed1985

Interethnic dissociation between debrisoquine and desipramine hydroxylation.

Chinese and Caucasian volunteers who had previously participated in a single dose desipramine pharmacokinetic study underwent debrisoquine hydroxylation phenotyping. After a single 10-mg oral dose of debrisoquine, urinary concentrations of the drug and its major metabolite, 4-hydroxy-debrisoquine (4-OHD), from an 8-hour collection were more variable in the Caucasians. Compared to the Chinese, the Caucasian subjects tended to excrete higher mean fractions of the dose as unchanged debrisoquine (10.9 +/- 8.8% vs. 6.3 +/- 2.6%) and 4-OHD (15.9 +/- 13.0% vs. 9.7 +/- 7.7%), although given the high variability the differences did not reach significance. The "metabolic ratio" of urinary debrisoquine to 4-OHD was less than 3 in all 20 subjects, indicating extensive debrisoquine hydroxylation in every volunteer, including two Chinese individuals known to display slow clearance of desipramine. Contrary to expectation, debrisoquine hydroxylation did not correlate with total or hydroxylation clearance of desipramine in either ethnic group singly or combined. This finding is not consistent with assumptions about the genetic equivalence of the primary metabolic pathways of debrisoquine and desipramine.

Adult↗
PubMed2002

4-Hydroxylation of debrisoquine by human CYP1A1 and its inhibition by quinidine and quinine.

A panel of 15 recombinant cytochromes P450 expressed in human B-lymphoblastoid cells was used to study debrisoquine 4-hydroxylation. Both CYP2D6 and CYP1A1 carried out the reaction. The apparent K(m) (micromolar) and V(max) (picomoles per minute per picomole of P450) for CYP2D6 were 12.1 and 18.2 and for CYP1A1 were 23.1 and 15.2, respectively. CYP1A1 debrisoquine 4-hydroxylase was inhibited by the CYP1A1 inhibitor alpha-naphthoflavone and the CYP1A1 substrate 7-ethoxyresorufin. Additionally and surprisingly, this reaction was also inhibited by quinidine and quinine, with respective IC(50) values of 1.38 +/- 0.10 and 3.31 +/- 0.14 microM, compared with those for CYP2D6 debrisoquine 4-hydroxylase of 0.018 +/- 0.05 and 3.75 +/- 2.07 microM, respectively. Anti-CYP1A1 monoclonal antibody (mAb) 1-7-1 abolished CYP1A1 debrisoquine hydroxylase and anti-CYP2D6 mAb 50-1-3 eradicated CYP2D6 debrisoquine 4-hydroxylase. Three further CYP2D6-specific reactions were tested: dextromethorphan O-demethylation, bufuralol 1'-hydroxylation, and sparteine dehydrogenation. The CYP2D6 specificity, judged by the CYP2D6/CYP1A1 activity ratios was 18.5, 7.0, 6.0, and 1.6 for dextromethorphan, bufuralol, sparteine, and debrisoquine, respectively. Thus, debrisoquine is not a specific CYP2D6 substrate and quinidine is not a specific CYP2D6 inhibitor. These findings have significant implications for the conduct of in vitro drug metabolism inhibition studies and underscore the fallacy of "specific chemical inhibitors" of a supergene family of enzymes that have overlapping substrate specificities. The use of highly specific mAbs in such studies is mandated. It is unclear as yet whether these findings have implications for the relationship between CYP2D6 genotype and in vivo debrisoquine 4-hydroxylase activity.

Adrenergic Agents↗
PubMed1990

Polymorphism of debrisoquine 4-hydroxylation and family studies of poor metabolizers in Chinese population.

Debrisoquine hydroxylation capacity determined as the ratio of debrisoquine over 4-OH-debrisoquine in 8-h urine after a single dose (10 mg) was studied in 140 unrelated Chinese Han subjects and 2 families of poor metabolizers (PM) of debrisoquine. In the 140 Chinese subjects the frequency of PM was found to be 1.43% (2/140), much lower than the 5-10% in white population reported. No sex difference was shown on the hydroxylation of debrisoquine. The recoveries of debrisoquin, 4-OH-debrisoquine in 8-h urine were 16 +/- 11 and 13 +/- 6%, respectively. None of the parents in the 2 families was PMs. Phenotype distribution in each family and population was consistent with the hypothesis that debrisoquine 4-OH-hydroxylation activity is under diallelic, monogenetic control, with the PM phenotype inheriting in an autosomal recessive trait.

Adolescent↗
PubMed1991

Debrisoquine oxidation phenotype during neuroleptic monotherapy.

The debrisoquine oxidation phenotype was determined in 91 schizophrenic patients on monotherapy with different neuroleptics and in 67 untreated healthy volunteers. The prevalence of poor metabolizers of debrisoquine was significantly higher in the patients (46.2%) than in the healthy subjects (7.5%). Treatment with phenothiazine antipsychotics (chlorpromazine, levomepromazine and thioridazine) was associated with a higher debrisoquine metabolic ratio than treatment with haloperidol. On the other hand, treatment with clothiapine appeared not to interfere with debrisoquine oxidation. Oral administration of 50 mg thioridazine daily to 8 healthy subjects resulted in a marked increase in the debrisoquine metabolic ratio and 4 of them were transformed into phenotypically poor metabolizers. The results confirm the fact that phenothiazines, and to a lesser extent haloperidol, inhibit the oxidative metabolism of debrisoquine. They show also that clothiapine administration does not disturb the debrisoquine metabolic ratio.

Adult↗