Debrisoquine Hydroxylation Phenotype Research Articles

CYP2D6 genotype and debrisoquine hydroxylation phenotype in Cubans and Nicaraguans

CYP2D6 genotype and debrisoquine metabolic ratio (MR) were analyzed in 133 Nicaraguan Mestizos (NMs) and 260 Cubans divided into Cuban Mestizos (CMs) and White Cubans (WCs). The frequencies of poor metabolizers (MR12.6) were 6% in NMs, 3.9% in CMs and 5.3% in WCs. The frequencies of ultrarapid metabolizers (MR0.1) were 0% in NMs, 2.3% in CMs and 5.3% in WCs. Mean (±s.d.) MR among extensive metabolizers (MR<12.6) was higher in NMs (1.5±1.6; n=118) than in CMs (1.0±1.3; n=124; P<0.001) and WCs (0.7±1.0; n=124; P<0.001). MR correlated with the 'activity score' of CYP2D6 genotypes (P<0.05; r=-0.55). Mean MR was higher among NMs than WCs and CMs for groups classified as 1 (P<0.05) or 2 (P<0.01) 'activity score'. In addition, mean (±s.d.) MR was higher among subjects carrying CYP2D6*17 than in CYP2D6 wt/wt (P<0.001). The CYP2D6*10 allele was higher in NMs (3.1%) than in CMs (0.8%; P<0.05) and WCs (0.4%; P<0.05). CYP2D6*17 allele was higher in CMs (10.2%) than WC (2.7%; P<0.005) and NMs (0%). Thus, the variability in CYP2D6 phenotypes found may be related to differences in allele frequency among groups (that is, CYP2D6*10 and *17 highest in NMs and CMs, respectively). However, the influence of environmental factors or alleles different than those studied here cannot be ruled out.

Pharmacogenetics of Debrisoquine and its Use as a Marker For CYP2D6 Hydroxylation Capacity

Debrisoquine hydroxylation polymorphism is by far the most thoroughly studied genetic polymorphism of the CYP2D6 drug-metabolizing enzyme. Debrisoquine hydroxylation phenotype has been the most used test in humans to evaluate CYP2D6 activity. Two debrisoquine hydroxylation phenotypes have been described: poor and extensive metabolizers. A group with a very low debrisoquine metabolic ratio within the extensive metabolizers, named ultrarapid metabolizers, has also been distinguished. This CYP2D6 variability can be for a large part alternatively determined by genotyping, which appears to be of clinical importance given CYP2D6 involvement in the metabolism of a large number of commonly prescribed drugs. CYP2D6 pharmacogenetics may then become a useful tool to predict drug-related side effects, interactions or therapeutic failures. However, a number of reasons appear to have made research into this field lag behind. The present review focuses on the relevance of genetics and environmental factors for determining debrisoquine hydroxylation phenotype, as well as the relevance of CYP2D6 genetic polymorphism in psychiatric patients treated with antipsychotic drugs.

Altered Distribution of the Debrisoquine Oxidative Phenotypes in Children with Type 1 Diabetes mellitus

Objective: The recently observed increase in the incidence of type 1 diabetes mellitus (Type 1 DM) suggests a major role of environmental factors in the etiopathogenesis of the disease. The individual variation in cytochrome P₄₅₀IID6 may influence the individual susceptibility to environmentally linked diseases. We aimed to evaluate the prevalence of cytochrome P₄₅₀IID6 phenotypes in Hungarian children with Type 1 DM (n = 69) compared to healthy controls (n = 100). Methods: Debrisoquine was administered orally and debrisoquine hydroxylation phenotype was determined as a metabolic ratio of urinary recovered debrisoquine and 4-hydroxydebrisoquine. Results: Eight of the 100 healthy subjects (8%) and 15 of the 69 diabetic children (22%) (p < 0.05) had cytochrome P₄₅₀IID6 poor metabolizer phenotype (metabolic ratio ≧12.6). Conclusion: Cytochrome P₄₅₀IID6’s activity may play a role in the development of Type 1 DM.

Metabolism of citalopram enantiomers in CYP2C19/CYP2D6 phenotyped panels of healthy Swedes.

To investigate pharmacokinetics of the enantiomers of citalopram (CT) and its metabolites desmethylcitalopram (DCT) and didesmethylcitalopram (DDCT) in Swedish healthy volunteers in relation to CYP2C19 and CYP2D6 geno- and phenotypes. Racemic CT was given for seven days to panels with different genotypes and the following mephenytoin (Me) and debrisoquine (De) hydroxylation phenotypes: EMDe/EMMe, PMDe/EMMe, EMDe/PMMe (n = 6 in all groups), and one PMDe/PMMe subject. Blood sampling was carried out during day 7, and all urine was collected for 12 h after the last dose of CT. The AUC of S-CT was significantly higher in the EMDe/PMMe panel compared to the EMDe/EMMe and PMDe/EMMe panels (P < 0.05), whereas the AUC of R-CT did not differ between the panels. Similar differences, although they did not reach statistical significance, were noted for S-DCT and R-DCT. The enantiomers of DDCT were not quantifiable in PMDe, and there was no difference in DDCT enantiomer concentrations between the other two panels. A PMDe/PMMe subject stopped taking CT after five days due to severe adverse effects. Based on two time points, this subject had a very long CT half-life of 95 h. The value of 1.0 for the S/R ratio of the CT trough in this subject was similar to the mean S/R CT trough ratio of the EMDe/PMMe panel, but higher than the S/R CT ratio of the EMDe/EMMe panel (0.56; 95% CI 0.49-0.63) and the PMDe/EMMe panel (0.44; 95% CI 0.31-0.57). Thus the latter two phenotypes eliminated S-CT more rapidly via CYP2C19. An adverse effect described as an 'alcohol hangover' feeling was reported by one subject from each of the three panels. These individuals had the highest concentrations of both CT enantiomers. The AUC of S-, but not R-(CT) was found to be significantly higher in PM of mephenytoin compared to EMs, PMs may need a lower dosage of CT.

Effect of thioridazine dosage on the debrisoquine hydroxylation phenotype in psychiatric patients with different CYP2D6 genotypes.

Sixteen hospitalized white European Spanish psychiatric patients treated with thioridazine alone were studied with respect to CYP2D6 genotype, debrisoquine metabolic ratio (MR), and the plasma levels of thioridazine and its metabolites mesoridazine and sulforidazine. After decreasing the dose of thioridazine the debrisoquine MR and thioridazine plasma levels were redetermined. At the initial determination (regular clinical doses, 20-300 mg/day), 14 of 16 patients (88%) were classified as poor metabolizers of debrisoquine (PMs). However, after complete withdrawal of thioridazine in 10 patients, all 10 became extensive metabolizers except two who were genotypically PMs (*4/*4). The inhibition of debrisoquine metabolism was genotype dependent. All patients with wt/wt genotype treated with a dose 150 mg/d were phenotypically PMs, all patients with wt/*4 genotype treated with a dose of 50 mg/d or greater were PMs. The debrisoquine MR from all dose changes correlated with the dose (p < 0.001) and plasma level (p < 0.001) of thioridazine. The CYP2D6 hydroxylation capacity was inhibited by thioridazine as determined by the debrisoquine MR. This inhibition was reversible by thioridazine withdrawal, and thus seems to be dose dependent and related to CYP2D6 genotype. One must consider the effects of thioridazine dosage on CYP2D6, because it may influence the metabolism of concomitant drugs or produce clinically important adverse effects such as cardiotoxicity. An awareness of this problem and cautious dosage adjustment of other drugs metabolized by the same enzyme are recommended during treatment with thioridazine.

Interethnic differences in drug metabolism: influence of genetic and environmental factors on debrisoquine hydroxylation phenotype

Genetic and environmental factors are determinants of the interindividual and interethnic variability in drug metabolism. The metabolism of several important drugs (e.g. haloperidol) cosegregates with that of debrisoquine. Thus, interethnic differences in debrisoquine hydroxylation polymorphism (CYP2D6) might be partly responsible for the variation in haloperidol disposition between races. The influence of tobacco, ethanol, caffeine, gender, and oral contraceptive use on the debrisoquine metabolic ratio (MR) has been analyzed in 633 Spanish healthy volunteers. MR was also determined in panels of healthy volunteers. 18 smokers were studied during a tobacco abstinence period, and 31 women three times during the same menstrual cycle. Among EMs, debrisoquine MR was significantly (P < 0.05) lower during smoking cessation (mean antilog +/- SD, 0.48 +/- 0.29) compared to a smoking period (0.61 +/- 0.23). During the lutheal phase of the menstrual cycle, debrisoquine MR was also significantly (P < 0.01) lower (0.33 +/- 0.41) compared to the ovulatory-phase (0.41 +/- 0.34) and the phase before ovulation (0.44 +/- 0.36). Among EMs, it is suggested that debrisoquine MR may be modified by tobacco smoking and sexual hormones. The clinical relevance of these findings remains unclear.

Disposition and bioavailability of the β1‐adrenoceptor antagonist talinolol in man

In an open randomized crossover study, the pharmacokinetics and bioavailability of the selective beta 1-adrenoceptor antagonist talinolol (Cordanum--Arzneimittelwerk Dresden GmbH, Germany) were investigated in twelve healthy volunteers (five female, seven male; three poor and nine extensive metabolizers of the debrisoquine hydroxylation phenotype) after intravenous infusion (30 mg) and oral administration (50 mg), respectively. Concentrations of talinolol and its metabolites were measured in serum and urine by HPLC or GC-MS. At the end of infusion a peak serum concentration (Cmax) of 631 +/- 95 ng mL-1 (mean +/- SD) was observed. The area under the serum concentration-time curve from zero to infinity (AUC0-infinity) was 1433 +/- 153 ng h mL-1. The following parameters were estimated: terminal elimination half life (t 1/2), 10.6 +/- 3.3 h; mean residence time, 11.6 +/- 3.1 h; volume of distribution, 3.3 +/- 0.5 L kg-1; and total body clearance, 4.9 +/- 0.6 mL min-1 kg-1. Within 36 h 52.8 +/- 10.6% of the administered dose was recovered as unchanged talinolol and 0.33 +/- 0.18% as hydroxylated talinolol metabolites in urine. After oral administration a Cmax of 168 +/- 67 ng mL-1 was reached after 3.2 +/- 0.8 h. The AUC0-infinity was 1321 +/- 382 ng h mL-1. The t 1/2 was 11.9 +/- 2.4 h. 28.1 +/- 6.8% of the dose or 55.0 +/- 11.0% of the bioavailable talinolol was eliminated as unchanged talinolol and 0.26 +/- 0.17% of the dose as hydroxylated metabolites by kidney. The absolute bioavailability of talinolol was 55 +/- 15% (95% confidence interval, 36-69%).(ABSTRACT TRUNCATED AT 250 WORDS)

Reproducibility over time of mephenytoin and debrisoquine hydroxylation phenotypes.

Mephenytoin and debrisoquine hydroxylation phenotypes were determined twice in 15 Spanish healthy volunteers with an interval of about one year. The phenotype assignment did not change in any subject for either debrisoquine or mephenytoin. Among extensive metabolisers of mephenytoin, there was a slight increase (P = 0.04) of the mephenytoin-S/R enantiomeric ratio over the study period. The family members of a poor metaboliser of mephenytoin were phenotyped, and the heterozygous extensive metabolisers were found to have higher mephenytoin-S/R ratios than other extensive metabolisers suggesting a correlation between the genotype and the S/R ratio.

Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects: polymorphism in RFLP and DNA sequence of CYP2D6.

Debrisoquin hydroxylation phenotype was determined in 124 Chinese persons living in Taiwan, and two poor metabolizers were identified with a urinary metabolic ratio (MR) greater than 12.6. The other subjects, extensive metabolizers, showed a normal frequency distribution of log(MR). Most subjects (50%) showed a 44/29 kb pattern in restriction fragment length polymorphism (RFLP) analysis with use of Xba I, and 30% and 15% of the subjects exhibited a homozygous 29/29 kb and 44/44 kb pattern, respectively. Among extensive metabolizers, subjects with the 44/44 kb pattern had a significant higher log(MR) than those with the 44/29 pattern, and the log(MR) of the subjects with the 44/29 kb pattern was significantly higher than that of the subjects with 29/29 kb pattern. All nine exons and intron 3 of C gamma P2D6 were amplified with polymerase chain reaction (PCR) and sequenced for four extensive metabolizers. Two major polymorphisms were found: one at position 188 of exon 1 and the other at position 4268 in exon 9. With PCR and endonuclease digestion, polymorphisms at exon 1, intron 3, and exon 9 were investigated. Only two of 254 alleles showed a heterozygous guanine at 1934 base pairs (G1934) to adenine (A) mutation, commonly found in white poor metabolizers. Approximately 70% of alleles showed thymine at 188 base pairs (T188), and 76% showed cytosine at 4268 base pairs (C4268) instead of C188 and G4268, as is found in most white subjects. Subjects with T188 or C4268 showed a significant higher log(MR) than subjects with homozygous C188 and G4268. The C/T188, G/A1934, G/C4268, and RFLP polymorphisms may explain the interracial variations between Chinese and white subjects, as well as the genetic variations among Chinese subjects.

Debrisoquine Hydroxylation Phenotypes of

Debrisoquine hydroxylation phenotype was determined in 22 psychiatric patients who had previously developed exceptionally high serum antidepressant (AD) concentrations, and in 22 sex-, age-, and dose-matched counterparts who had low to normal serum AD levels. The patients were recruited from 641 subjects in whom serum AD levels were monitored. In each AD level group, 16 patients had been treated with tricyclic antidepressants (amitriptyline, doxepin, trimipramine, imipramine, clomipramine) and 6 with mianserin. Eight poor metabolizer (PM) phenotypes (debrisoquine/hydroxydebrisoquine ratio in 6-hour urine ≥ 41.5) were identified in the high AD level group, but only two in the group with low to normal AD level (p = 0.03, Fisher's test). Comedications in the two study groups did not differ markedly from each other and could not, therefore, explain the greater frequency of PMs among the patients with high serum AD levels. Three of 6 mianserin patients, who had developed high serum AD levels, were PMs. This high proportion of PMs raises the question of a possible involvement of the same metabolic pathway (cytochrome P-450IID6 isoenzyme) also in mianserin hydroxylation. The results suggest further that during AD therapy with standard dosage, PM phenotypes are at special risk for high serum AD concentrations and, consequently, for clinical symptoms of toxicity.

Haloperidol disposition is dependent on the debrisoquine hydroxylation phenotype: increased plasma levels of the reduced metabolite in poor metabolizers.

We have previously shown that the disposition of haloperidol is decreased in poor (PM) compared to extensive (EM) metabolizers of debrisoquine. We now report that the plasma levels of the reduced metabolite of haloperidol, after a single 2- or 4-mg oral dose of the parent drug, are significantly higher in PM than in EM of debrisoquine. As PM have higher concentrations of haloperidol than EM, more of the reduced metabolite should be formed, since the formation of reduced haloperidol from haloperidol seems to be independent of the debrisoquine hydroxylase (cytochrome P4502D6) activity. Another reason to explain the increased metabolite levels in PM may be a decreased reoxidation of the reduced metabolite to haloperidol, as this reaction is catalyzed by cytochrome P4502D6. A third reason might be that reduced haloperidol is transformed to other metabolites by this enzyme.

Haloperidol disposition is dependent on debrisoquine hydroxylation phenotype.

To investigate the importance of genetic factors for the regulation of haloperidol metabolism, we studied the disposition of a single oral dose of this drug in a panel of six extensive (EM) and six poor (PM) metabolizers of debrisoquine. PM eliminated haloperidol significantly slower than EM, the plasma half-life being longer (mean 29.4 +/- S.D. 4.2 and 16.3 +/- 6.4 h; p less than 0.01) and the clearance lower (1.16 +/- 0.36 and 2.49 +/- 1.31 L/h/kg; p less than 0.05). A 4-mg dose of haloperidol was given to the first three PM, but all three developed side effects, and a 2-mg dose had to be given to the next three PM subjects. All EM received 4 mg haloperidol. The disposition of haloperidol is thus associated with the genetically determined capacity to hydroxylate debrisoquine. PM of debrisoquine (7% of Caucasian populations) might, therefore, on common doses of haloperidol, achieve high plasma concentrations and thereby have an increased risk of side effects. At the other extreme, very rapid metabolizers may need increased doses of haloperidol.

Analysis of the CYP2D6 gene in relation to debrisoquin and desipramine hydroxylation in a Swedish population.

The molecular basis of polymorphic debrisoquin hydroxylation was studied in 223 Swedish white subjects, 187 extensive metabolizers and 36 poor metabolizers phenotyped with debrisoquin and desipramine. Restriction fragment length polymorphism (RFLP) analysis of the CYP2D6 gene revealed that 52% of unrelated poor metabolizers were homozygous for Xba I 29 kb fragment, and only 8% had two mutant alleles detected with RFLP. Allele-specific polymerase chain reaction (PCR)-based DNA amplification, however, revealed that all but one of the poor metabolizers had two mutant alleles of the CYP2D6A or CYP2D6B type or both. Extensive metabolizers who were heterozygous for wild-type and CYP2D6B genes had metabolic ratios for debrisoquin and desipramine that were higher than those of subjects who were homozygous for the wild-type gene. The 16 + 9 kb Xba I RFLP pattern was associated with the poor metabolizer phenotype and CYP2D6B mutations. Three extremely rapid metabolizers of debrisoquin had a 44 kb Xba I fragment that did not carry either CYP2D6A or CYP2D6B mutations. In conclusion, in the Swedish population studied, allele-specific PCR amplification allowed prediction of the debrisoquin hydroxylation phenotype with 99% accuracy.

N‐acetylation and debrisoquine hydroxylation polymorphisms in patients with Gilbert's syndrome.

1. N-acetylation and debrisoquine hydroxylation phenotypes were determined in 54 patients with Gilbert's syndrome and in 247 (sulphamethazine) and 76 (debrisoquine) non-related healthy volunteers. 2. Forty (74.1%) of the patients and 135 (54.7%) of the healthy volunteers were slow acetylators (chi 2 = 6.87). In the patients, the cumulative urinary excretion of sulphamethazine up to 6 h (Ae(0,6)) was significantly lower. No differences in the frequency of debrisoquine poor metabolizers were observed: Gilbert's syndrome 5/54 (9.3%), healthy volunteers 5/76 (6.6%). The metabolic ratios were similar in both groups as well as the urinary recoveries of debrisoquine and its 4-hydroxy metabolite. 3. Gilbert's syndrome seems to be related in some way to N-acetylation but not to the debrisoquine hydroxylation polymorphism.

Research of a genetic predisposition to primary bronchopulmonary cancer by the study of debrisoquine hydroxylation phenotype : Pilliere F, Dalphin J-C, De Palmas J, Duchet J.-C, Brochard P. Department de Medecine du Travail, Centre Hospitalier Intercommunal, 40, avenue de Verdun, 94010 Creteil Cedex. Arch Mal Prof. Med Trav Secur Soc 1990;51:11–16

Research of a genetic predisposition to primary bronchopulmonary cancer by the study of debrisoquine hydroxylation phenotype : Pilliere F, Dalphin J-C, De Palmas J, Duchet J.-C, Brochard P. Department de Medecine du Travail, Centre Hospitalier Intercommunal, 40, avenue de Verdun, 94010 Creteil Cedex. Arch Mal Prof. Med Trav Secur Soc 1990;51:11–16

Debrisoquine oxidation polymorphism in a Tasmanian population

The debrisoquine hydroxylation phenotype was studied in 152 unselected healthy Tasmanian subjects, who were mostly Caucasians of British ancestry. Following a 10 mg oral dose of debrisoquine (D), the ratio of D/4-hydroxydebrisoquine excreted in 8-h urine (metabolic ratio, MR) was determined. MR values were bimodally distributed. Thirteen subjects (8.6%) had MR values from 13.8 to 93.3 and were considered to be poor metabolisers of D, while the others were extensive metabolisers with MR values of 0.04 to 5.4. The D hydroxylation phenotype was not associated with sex. These findings confirm the constancy of D polymorphism in a Caucasian population even after migration to another country.

Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype

The pharmacokinetics of thioridazine and its metabolites were studied in 19 healthy male subjects: 6 slow and 13 rapid hydroxylators of debrisoquin. The subjects received a single 25 mg oral dose of thioridazine, and blood samples were collected during 48 hours. Concentrations of thioridazine and metabolites in serum were measured by HPLC. Slow hydroxylators of debrisoquin obtained higher serum levels of thioridazine with a 2.4-fold higher Cmax and a 4.5-fold larger AUC(0-infinity) associated with a twofold longer half-life compared with that of rapid hydroxylators. The side-chain sulphoxide (mesoridazine) and sulphone (sulphoridazine), which are active metabolites, appeared more slowly in serum and had lower Cmax values, but comparable AUC. The thioridazine ring-sulphoxide attained higher Cmax and 3.3-fold higher AUC in slow hydroxylators than in rapid hydroxylators of debrisoquin. Thus the formation of mesoridazine from thioridazine and the 4-hydroxylation of debrisoquin seem to be catalyzed by the same enzyme, whereas the formation of thioridazine ring-sulphoxide is probably formed mainly by another enzyme.

Debrisoquine oxidation phenotype and susceptibility to lung cancer [letter; comment

British Journal of Clinical PharmacologyVolume 30, Issue 4 p. 653-656 Free Access Debrisoquine oxidation phenotype and susceptibility to lung cancer [letter; comment] AR Boobis, AR Boobis Academic Department of Medicine, Royal Free Hospital School of Medicine, London.Search for more papers by this authorDS Davies, DS Davies Academic Department of Medicine, Royal Free Hospital School of Medicine, London.Search for more papers by this author AR Boobis, AR Boobis Academic Department of Medicine, Royal Free Hospital School of Medicine, London.Search for more papers by this authorDS Davies, DS Davies Academic Department of Medicine, Royal Free Hospital School of Medicine, London.Search for more papers by this author First published: October 1990 https://doi.org/10.1111/j.1365-2125.1990.tb03832.xCitations: 5AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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A family study of genetic and environmental factors determining polymorphic hydroxylation of debrisoquine. Clin. Pharmac. Ther., 38, 394– 401. Citing Literature Volume30, Issue4October 1990Pages 653-656 ReferencesRelatedInformation

Alfentanil clearance is independent of the polymorphic debrisoquin hydroxylase.

Because alfentanil has been shown to inhibit debrisoquin hydroxylase in vitro, and there is considerable variability in the reported elimination clearance of alfentanil, the possible influence of the debrisoquin metabolic phenotype on the elimination clearance of alfentanil was studied. The disposition of alfentanil was determined after rapid intravenous administration to four extensive debrisoquin metabolizers and three poor debrisoquin metabolizers. Debrisoquin hydroxylation phenotype was determined using the urinary dextromethorphan/dextrorphan metabolic ratio test. The disposition of alfentanil was characterized by a three-compartment open mammillary model. There was no relationship between the dextromethorphan/dextrorphan metabolic ratio and the elimination clearance of alfentanil despite a nearly seven hundred-fold range of the metabolic ratio in the seven volunteers. This indicates that the variability in the elimination clearance of alfentanil is not due to the polymorphism of debrisoquin hydroxylase. Nor is this variability due to variable hepatic blood flow because in this study alfentanil clearance was not related to indocyanine green clearance.

E-10-hydroxynortriptyline: effects and disposition of a potential novel antidepressant.

Nortriptyline is one of the most studied antidepressants, and a therapeutic plasma concentration interval has been established (Sjoqvist et al. 1980). When similar doses of nortriptyline are given, the plasma levels vary extensively among individual patients (Sjoqvist, this volume). This is due to the great variation in the liver cytochrome P-450 enzyme, which hydroxylates nortriptyline. In several studies both in vivo and in vitro, we have shown that E-10-hydroxylation of nortriptyline covaries with the debrisoquin hydroxylation phenotype (see Sjoqvist, this volume).