Adrián LLerena | Universidad de Extremadura (original) (raw)
Papers by Adrián LLerena
Global precision medicine demands characterization of drug metabolism and phenotype variation in ... more Global precision medicine demands characterization of drug metabolism and phenotype variation in diverse populations, including the indigenous societies. A related question is the extent to which CYP450 drug metabolizing enzyme genotype and phenotype data are concordant and whether they can be used interchangeably. These issues are increasingly debated as precision medicine continues to expand as a popular research topic worldwide. We report here the first study in clinically relevant CYP450 drug metabolism phenotypes and genotypes in Mexican Amerindian indigenous subjects. In a large sample of 450 unrelated and medication free Mexican Amerindian indigenous healthy persons from four Mexican states (Chihuahua, Durango, Nayarit, and Sonora), we performed multiplexed phenotyping for the CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 drug metabolizing enzymes using the CEIBA cocktail and genotyped the same pathways for functional polymorphic variation. Remarkable interindividual variability was found for the actual drug metabolizing capacity of all the enzymes analyzed, and, more specifically, the metabolic ratios calculated were significantly different across individuals with different number of active alleles for CYP2C9, CYP2C19, and CYP2D6. The drug metabolizing capacity ''pre-dicted'' from the genotype determined was not in accordance with the actual capacity ''measured'' by phenotyping in several individuals for CYP2C9, CYP2C19, and CYP2D6. Consequently, a more extensive genotyping of the main CYP enzymes, including rare variants, together with the analysis of the actual drug metabolizing capacity using an appropriate phenotyping approach will add valuable information for accurate drug metabolism studies, especially useful in understudied populations such as Mexican Amerindians. In sum, this study demonstrates that current personalized medicine strategies based on ''predicted'' phenotype from genotyping of alleles with high frequency in European populations are not adequate for Mestizos and Native American populations.
Intra-and/or inter-individual variability in drug response is mainly a result of either sub-thera... more Intra-and/or inter-individual variability in drug response is mainly a result of either sub-therapeutic or supratherapeutic plasma levels of the active drugs and their metabolites, with this variability mainly being influenced by differences in the rate of drug metabolism. Indeed, drug metabolism is largely determined by genetic polymorphism in the CYP enzymes, which are responsible for approximately 85% of the drug metabolism process. However, this genetic heterogeneity can accurately predict actual drug metabolizing capacity (oxidation phenotype) for some individuals: poor metabolizers (PMs), who cannot produce the drug metabolizing enzymes, and 20% of ultra-rapid metabolizers. According to EMA recommendations, pheno-typing procedures for drug interaction studies and clinical research are therefore required to obtain actual data on the main CYP enzymes. With this purpose, cocktail phenotyping approaches give information on the activity of different CYPs in just one experiment. In this review, the issues related to the phenotyping of the main CYP enzymes are reviewed, and the current in vivo phenotyping cocktails are analysed: the sampling procedures, probe drugs utilized, analytical techniques and main applications are also discussed. Based on this analysis, a fully validated cocktail approach to measure the metabolic activity of the main CYP enzymes and drug transporters is still required. This novel approach should fulfil certain conditions: a faster and simpler analytical methodology to obtain information on several CYPs in one experiment , minimal sample amounts, and minimal doses of optimal probe drugs.
European journal of clinical pharmacology, Jan 1, 2008
Purpose CYP2C8 seems to be involved in diclofenac 5-hydroxylation, while, in vitro, the 4′-hydrox... more Purpose CYP2C8 seems to be involved in diclofenac 5-hydroxylation, while, in vitro, the 4′-hydroxylation and 3′-hydroxylation seem to be mediated mainly by CYP2C9. We have demonstrated the relevance of CYP2C9 genotypes for diclofenac 4′-hydroxylation in healthy volunteers, so that the present study was aimed at analyzing the role of both CYP2C8 and CYP2C9 genotypes on diclofenac metabolism, as well as determining the CYP2C8 allele frequencies and their relationship with CYP2C9 variants. Methods A group of 142 healthy white Spanish volunteers was studied. Previously, 102 of these subjects had been phenotyped with diclofenac and genotyped for CYP2C9. The CYP2C8 genotypes were determined by allele-specific PCR-RFLP methods. The urinary concentrations of diclofenac and its main metabolites were analysed using an HPLC-UV method after the administration of a single oral dose of diclofenac as described previously for part of the population studied here. Results The diclofenac/5-hydroxydiclofenac urinary concentration ratio was higher in individuals carrying a CYP2C8*3 or CYP2C8*4 allele than in those homozygous for wild-type allele CYP2C8*1 (P < 0.05). Moreover, approximately 93% of the subjects with a CYP2C8*3 allele also carried a CYP2C9*2, and 80% of the subjects that had CYP2C9*2 variant also carried a CYP2C8*3. In addition, the four CYP2C9*2/*2 individuals were CYP2C8*3/*3. Conclusions This is the first study showing the influence of CYP2C8 genotypes on diclofenac metabolism in vivo. The linkage disequilibrium between CYP2C8*3 and CYP2C9*2 alleles was confirmed in this Spanish population.
European Journal of Clinical Pharmacology, 1989
Acetylator phenotype has been determined using sulphamethazine in 100 patients with Parkinson's d... more Acetylator phenotype has been determined using sulphamethazine in 100 patients with Parkinson's disease and in 93 age-matched normal control subjects. Sixty-nine patients and 54 control subjects were classified as slow acetylators (NS). No relation was found among acetylator polymorphism and age at onset or clinical stage of disease. Amongst slow acetylators, the percentage of acetylated sulphamethazine in plasma was significantly lower in patients than in controls. Despite this finding, the results do not support any relationship between acetylator polymorphism and the risk of developing Parkinson's disease.
European Journal of Psychological Assessment, 2002
Estudio del polimorfismo de debrisoquina en una muestra de la población cubana Rev Cubana Farm 20... more Estudio del polimorfismo de debrisoquina en una muestra de la población cubana Rev Cubana Farm 2005; 39(1) Facultad de Ciencias Médicas "General Calixto García" Estudio del polimorfismo de debrisoquina en una muestra de la población cubana
Annals of Medicine, 1990
The oxidative polymorphism of debrisoquine has been determined in 125 patients with bladder cance... more The oxidative polymorphism of debrisoquine has been determined in 125 patients with bladder cancer and in 556 healthy control subjects; 96.6% of patients and 93.9% of controls with a metabolic ratio of debrisoquine less than 12.6 were classified as extensive metabolizers of debrisoquine (P = NS). The distribution of frequencies of metabolic ratio values tended to have lower values in the patients (P less than 0.05), reflecting a higher oxidative rate of debrisoquine in urothelioma patients that cannot be explained solely in terms of enzymatic induction by drugs, tobacco or alcohol. Patients with a high occupational risk for urothelioma had lower metabolic ratio values (P = 0.03). Our results suggest that oxidative polymorphism of debrisoquine might be related to the pathogenesis of bladder cancer.
Oncology, 1991
Oxidative polymorphism of debrisoquine (DBQ) was determined in 98 women with breast cancer (mean ... more Oxidative polymorphism of debrisoquine (DBQ) was determined in 98 women with breast cancer (mean age 59.2 years, SD 10.7; 18 were premenopausal when diagnosed), and in 446 healthy control women (mean age 25.4 years, SD 9.15). All of them were free of drug interactions with oxidation of DBQ. Ten patients (10.2%), all of them postmenopausal when diagnosed, and 423 controls (5.2%), with values for metabolic ratio of DBQ greater than 12.6, were classified as poor metabolizers (PM) of DBQ (p = 0.006). Relative risk for developing breast cancer among women with PM phenotype was 2.09 (95% confidence limits 0.97-4.48). The PM status of DBQ might be a secondary risk factor for breast cancer in postmenopausal women.
Pharmacological Research Communications, 1988
CYP2D6 polymorphism is related to absent (poor metabolizers, PMs) and normal/decreased (extensive... more CYP2D6 polymorphism is related to absent (poor metabolizers, PMs) and normal/decreased (extensive metabolizers, including ultrarapid metabolizers) metabolism of clinically important drugs. Moreover CYP2D6 is also involved in the metabolism of endogenous substrates in the brain which appear highly important for psychological functioning that may be related to normal and abnormal behavioral tendencies or psychopathology. Although there are contradictory results, a
Anales de medicina interna (Madrid, Spain : 1984), 1991
The acetylation phenotype was determined, by means of sulfamethazine measurement, in 87 patients ... more The acetylation phenotype was determined, by means of sulfamethazine measurement, in 87 patients (83 male) with confirmed bronchogenic carcinoma and in 93 healthy control patients (41 male) of equal ages. 48 patients and 54 controls were classified as being "slow acetylators" (Ch2 n.s.) When the persons were individually analysed by phenotype, it was confirmed that the patients showed a significantly lower rate of acetylated sulfamethazine than the control group (p less than 0.02), owing to the poor acetylation of patients with small-cell lung cancer. This difference should be confirmed by more detailed pharmacokinetic studies before regarding it as a possible interference of paraneoplasic type. The polymorphism acetylator cannot be considered a genetic marker related to the risk of having lung cancer.
Psychopharmacology series, 1993
European journal of clinical pharmacology, 1993
We have investigated the prevalence of poor metabolisers (PM) of S-mephenytoin in 373 unrelated, ... more We have investigated the prevalence of poor metabolisers (PM) of S-mephenytoin in 373 unrelated, healthy Spanish Caucasian subjects, based on the enantiomeric S/R mephenytoin ratio in urine collected 0-8 h and 24-32 h after intake of the racemic drug.
Acta psychiatrica Scandinavica, 1993
We administered the Karolinska Scales of Personality to 225 healthy subjects in Spain selected fr... more We administered the Karolinska Scales of Personality to 225 healthy subjects in Spain selected from a group of 925 individuals previously phenotyped with regard to their capacity to hydroxylate debrisoquine. A significant relationship was found between the scores in as many as 4 of the 15 subscales (psychic anxiety, psychasthenia, inhibition of aggression and socialization) and the debrisoquine hydroxylation capacity. Poor metabolizers were more anxiety-prone and less successfully socialized than extensive metabolizers of debrisoquine. This and a previous study among subjects in Sweden suggest that there may be a relationship between personality and the activity of the enzyme hydroxylating debrisoquine (cytochrome P4502D6). This polymorphic enzyme may have an endogenous neuroactive substrate or product, such as a biogenic neurotransmitter amine.
Pharmacology & toxicology, 1993
Mephenytoin and debrisoquine hydroxylation phenotypes were determined twice in 15 Spanish healthy... more 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.
Clinical pharmacology and therapeutics, 1993
Debrisoquin and S-mephenytoin hydroxylation phenotypes were determined in 72 Spanish psychiatric ... more Debrisoquin and S-mephenytoin hydroxylation phenotypes were determined in 72 Spanish psychiatric patients treated with neuroleptic or antidepressant agents. One patient (1.4%) was classified as a poor metabolizer of S-mephenytoin. Between both neuroleptic-and antidepressant-treated patients, the distribution of the debrisoquin metabolic ratio was shifted toward higher values compared with 54 drugfiee healthy subjects. Forty percent of patients treated with neuroleptics and 5% of patients treated with antidepressants were classified as poor metabolizers of debrisoquin. CTP2D6 genotype analysis in 36 neuroleptic-treated patients confirmed that the high metabolic ratios were attributable to inhibition of CYP2D6 and not to overrepresentation of subjects with poor metabolizer genotypes. In 48 selected Spanish drug-fiee subjects, CTP2D6 genotype predicted the phenotype with 95% accuracy. Neuroleptics and antidepressants interfere at therapeutic doses with phenotyping for CYP2D6 but not for S-mephenytoin hydroxylation capacity. In psychotropic-treated patients, genotyping provides a valuable tool for prediction of the CYP2D6 phenotype. (CLIN PHARMACOL THER 1993;54:606-11.) There are two established polymorphisms of drug oxidation, the debrisoquin-sparteine and the S-mephenytoin hydroxylation polymorphisms. Subjects with deficient metabolism are classified as poor metabolizers, whereas the remainder are extensive metabolizers. About 7% of white subjects are poor metabolizers of debrisoquin, whereas 3% are poor metabolizers of S-mephenytoin.' The poor metabolizer phenotype of
British journal of clinical pharmacology, 1994
A large interindividual variability has previously been demonstrated in the bioavailability, stea... more A large interindividual variability has previously been demonstrated in the bioavailability, steady-state plasma concentrations and clearance of clozapine, an atypical neuroleptic drug. To evaluate the importance of genetic factors in the metabolism of clozapine, its disposition after a single oral dose of 10 mg was studied in 15 healthy Caucasian volunteers. Five of the subjects were poor metabolisers (PM) of debrisoquine, five were PM of S-mephenytoin, and the remaining five were extensive metabolisers (EM) of both probe drugs. There was a 10-fold interindividual variation in Cmax and a 14-fold variation in AUC(0, 24) of clozapine among the 15 subjects studied. The mean (s.d.) Cmax was 117 (81) nmol 1-1 and the mean AUC(0,24) value was 890 (711) nmol 1-1 h. The value of t,,z varied 3-fold with a mean (s.d.) of 13.3 (5.0) h. There were no significant differences in the plasma concentrations or any of the pharmacokinetic parameters of clozapine between PM and EM of debrisoquine, or between the two S-mephenytoin hydroxylation phenotypes. We conclude that neither of the major genetic polymorphisms of oxidative drug metabolism contribute to the large interindividual variability in clozapine pharmacokinetics.
British journal of clinical pharmacology, 1994
British journal of clinical pharmacology, 1994
In a previous study we showed that the disposition of clozapine after a single oral dose is unrel... more In a previous study we showed that the disposition of clozapine after a single oral dose is unrelated to either debrisoquine or S-mephenytoin hydroxylation polymorphism. The same 14 healthy subjects studied in that investigation were given 150 mg of caffeine. The reciprocal of plasma clozapine AUC (0,24), was correlated with an index of the N3-demethylation of caffeine (r, = 0.84; P = 0.0024), used as a measure of cytochrome P4501A2 (CYP1A2) activity. Ni-and N7-demethylation indices of caffeine also reflect CYP1A2 activity and were also correlated with clozapine clearance (rs = 0.89 and 0.85; P = 0.0013 and 0.0023; respectively). No significant relationships with xanthine oxidase and N-acetyl transferase activity, also assessed by a caffeine test, were found. This study suggests that clozapine is metabolised by CYP1A2 to a major extent.
Global precision medicine demands characterization of drug metabolism and phenotype variation in ... more Global precision medicine demands characterization of drug metabolism and phenotype variation in diverse populations, including the indigenous societies. A related question is the extent to which CYP450 drug metabolizing enzyme genotype and phenotype data are concordant and whether they can be used interchangeably. These issues are increasingly debated as precision medicine continues to expand as a popular research topic worldwide. We report here the first study in clinically relevant CYP450 drug metabolism phenotypes and genotypes in Mexican Amerindian indigenous subjects. In a large sample of 450 unrelated and medication free Mexican Amerindian indigenous healthy persons from four Mexican states (Chihuahua, Durango, Nayarit, and Sonora), we performed multiplexed phenotyping for the CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 drug metabolizing enzymes using the CEIBA cocktail and genotyped the same pathways for functional polymorphic variation. Remarkable interindividual variability was found for the actual drug metabolizing capacity of all the enzymes analyzed, and, more specifically, the metabolic ratios calculated were significantly different across individuals with different number of active alleles for CYP2C9, CYP2C19, and CYP2D6. The drug metabolizing capacity ''pre-dicted'' from the genotype determined was not in accordance with the actual capacity ''measured'' by phenotyping in several individuals for CYP2C9, CYP2C19, and CYP2D6. Consequently, a more extensive genotyping of the main CYP enzymes, including rare variants, together with the analysis of the actual drug metabolizing capacity using an appropriate phenotyping approach will add valuable information for accurate drug metabolism studies, especially useful in understudied populations such as Mexican Amerindians. In sum, this study demonstrates that current personalized medicine strategies based on ''predicted'' phenotype from genotyping of alleles with high frequency in European populations are not adequate for Mestizos and Native American populations.
Intra-and/or inter-individual variability in drug response is mainly a result of either sub-thera... more Intra-and/or inter-individual variability in drug response is mainly a result of either sub-therapeutic or supratherapeutic plasma levels of the active drugs and their metabolites, with this variability mainly being influenced by differences in the rate of drug metabolism. Indeed, drug metabolism is largely determined by genetic polymorphism in the CYP enzymes, which are responsible for approximately 85% of the drug metabolism process. However, this genetic heterogeneity can accurately predict actual drug metabolizing capacity (oxidation phenotype) for some individuals: poor metabolizers (PMs), who cannot produce the drug metabolizing enzymes, and 20% of ultra-rapid metabolizers. According to EMA recommendations, pheno-typing procedures for drug interaction studies and clinical research are therefore required to obtain actual data on the main CYP enzymes. With this purpose, cocktail phenotyping approaches give information on the activity of different CYPs in just one experiment. In this review, the issues related to the phenotyping of the main CYP enzymes are reviewed, and the current in vivo phenotyping cocktails are analysed: the sampling procedures, probe drugs utilized, analytical techniques and main applications are also discussed. Based on this analysis, a fully validated cocktail approach to measure the metabolic activity of the main CYP enzymes and drug transporters is still required. This novel approach should fulfil certain conditions: a faster and simpler analytical methodology to obtain information on several CYPs in one experiment , minimal sample amounts, and minimal doses of optimal probe drugs.
European journal of clinical pharmacology, Jan 1, 2008
Purpose CYP2C8 seems to be involved in diclofenac 5-hydroxylation, while, in vitro, the 4′-hydrox... more Purpose CYP2C8 seems to be involved in diclofenac 5-hydroxylation, while, in vitro, the 4′-hydroxylation and 3′-hydroxylation seem to be mediated mainly by CYP2C9. We have demonstrated the relevance of CYP2C9 genotypes for diclofenac 4′-hydroxylation in healthy volunteers, so that the present study was aimed at analyzing the role of both CYP2C8 and CYP2C9 genotypes on diclofenac metabolism, as well as determining the CYP2C8 allele frequencies and their relationship with CYP2C9 variants. Methods A group of 142 healthy white Spanish volunteers was studied. Previously, 102 of these subjects had been phenotyped with diclofenac and genotyped for CYP2C9. The CYP2C8 genotypes were determined by allele-specific PCR-RFLP methods. The urinary concentrations of diclofenac and its main metabolites were analysed using an HPLC-UV method after the administration of a single oral dose of diclofenac as described previously for part of the population studied here. Results The diclofenac/5-hydroxydiclofenac urinary concentration ratio was higher in individuals carrying a CYP2C8*3 or CYP2C8*4 allele than in those homozygous for wild-type allele CYP2C8*1 (P < 0.05). Moreover, approximately 93% of the subjects with a CYP2C8*3 allele also carried a CYP2C9*2, and 80% of the subjects that had CYP2C9*2 variant also carried a CYP2C8*3. In addition, the four CYP2C9*2/*2 individuals were CYP2C8*3/*3. Conclusions This is the first study showing the influence of CYP2C8 genotypes on diclofenac metabolism in vivo. The linkage disequilibrium between CYP2C8*3 and CYP2C9*2 alleles was confirmed in this Spanish population.
European Journal of Clinical Pharmacology, 1989
Acetylator phenotype has been determined using sulphamethazine in 100 patients with Parkinson's d... more Acetylator phenotype has been determined using sulphamethazine in 100 patients with Parkinson's disease and in 93 age-matched normal control subjects. Sixty-nine patients and 54 control subjects were classified as slow acetylators (NS). No relation was found among acetylator polymorphism and age at onset or clinical stage of disease. Amongst slow acetylators, the percentage of acetylated sulphamethazine in plasma was significantly lower in patients than in controls. Despite this finding, the results do not support any relationship between acetylator polymorphism and the risk of developing Parkinson's disease.
European Journal of Psychological Assessment, 2002
Estudio del polimorfismo de debrisoquina en una muestra de la población cubana Rev Cubana Farm 20... more Estudio del polimorfismo de debrisoquina en una muestra de la población cubana Rev Cubana Farm 2005; 39(1) Facultad de Ciencias Médicas "General Calixto García" Estudio del polimorfismo de debrisoquina en una muestra de la población cubana
Annals of Medicine, 1990
The oxidative polymorphism of debrisoquine has been determined in 125 patients with bladder cance... more The oxidative polymorphism of debrisoquine has been determined in 125 patients with bladder cancer and in 556 healthy control subjects; 96.6% of patients and 93.9% of controls with a metabolic ratio of debrisoquine less than 12.6 were classified as extensive metabolizers of debrisoquine (P = NS). The distribution of frequencies of metabolic ratio values tended to have lower values in the patients (P less than 0.05), reflecting a higher oxidative rate of debrisoquine in urothelioma patients that cannot be explained solely in terms of enzymatic induction by drugs, tobacco or alcohol. Patients with a high occupational risk for urothelioma had lower metabolic ratio values (P = 0.03). Our results suggest that oxidative polymorphism of debrisoquine might be related to the pathogenesis of bladder cancer.
Oncology, 1991
Oxidative polymorphism of debrisoquine (DBQ) was determined in 98 women with breast cancer (mean ... more Oxidative polymorphism of debrisoquine (DBQ) was determined in 98 women with breast cancer (mean age 59.2 years, SD 10.7; 18 were premenopausal when diagnosed), and in 446 healthy control women (mean age 25.4 years, SD 9.15). All of them were free of drug interactions with oxidation of DBQ. Ten patients (10.2%), all of them postmenopausal when diagnosed, and 423 controls (5.2%), with values for metabolic ratio of DBQ greater than 12.6, were classified as poor metabolizers (PM) of DBQ (p = 0.006). Relative risk for developing breast cancer among women with PM phenotype was 2.09 (95% confidence limits 0.97-4.48). The PM status of DBQ might be a secondary risk factor for breast cancer in postmenopausal women.
Pharmacological Research Communications, 1988
CYP2D6 polymorphism is related to absent (poor metabolizers, PMs) and normal/decreased (extensive... more CYP2D6 polymorphism is related to absent (poor metabolizers, PMs) and normal/decreased (extensive metabolizers, including ultrarapid metabolizers) metabolism of clinically important drugs. Moreover CYP2D6 is also involved in the metabolism of endogenous substrates in the brain which appear highly important for psychological functioning that may be related to normal and abnormal behavioral tendencies or psychopathology. Although there are contradictory results, a
Anales de medicina interna (Madrid, Spain : 1984), 1991
The acetylation phenotype was determined, by means of sulfamethazine measurement, in 87 patients ... more The acetylation phenotype was determined, by means of sulfamethazine measurement, in 87 patients (83 male) with confirmed bronchogenic carcinoma and in 93 healthy control patients (41 male) of equal ages. 48 patients and 54 controls were classified as being "slow acetylators" (Ch2 n.s.) When the persons were individually analysed by phenotype, it was confirmed that the patients showed a significantly lower rate of acetylated sulfamethazine than the control group (p less than 0.02), owing to the poor acetylation of patients with small-cell lung cancer. This difference should be confirmed by more detailed pharmacokinetic studies before regarding it as a possible interference of paraneoplasic type. The polymorphism acetylator cannot be considered a genetic marker related to the risk of having lung cancer.
Psychopharmacology series, 1993
European journal of clinical pharmacology, 1993
We have investigated the prevalence of poor metabolisers (PM) of S-mephenytoin in 373 unrelated, ... more We have investigated the prevalence of poor metabolisers (PM) of S-mephenytoin in 373 unrelated, healthy Spanish Caucasian subjects, based on the enantiomeric S/R mephenytoin ratio in urine collected 0-8 h and 24-32 h after intake of the racemic drug.
Acta psychiatrica Scandinavica, 1993
We administered the Karolinska Scales of Personality to 225 healthy subjects in Spain selected fr... more We administered the Karolinska Scales of Personality to 225 healthy subjects in Spain selected from a group of 925 individuals previously phenotyped with regard to their capacity to hydroxylate debrisoquine. A significant relationship was found between the scores in as many as 4 of the 15 subscales (psychic anxiety, psychasthenia, inhibition of aggression and socialization) and the debrisoquine hydroxylation capacity. Poor metabolizers were more anxiety-prone and less successfully socialized than extensive metabolizers of debrisoquine. This and a previous study among subjects in Sweden suggest that there may be a relationship between personality and the activity of the enzyme hydroxylating debrisoquine (cytochrome P4502D6). This polymorphic enzyme may have an endogenous neuroactive substrate or product, such as a biogenic neurotransmitter amine.
Pharmacology & toxicology, 1993
Mephenytoin and debrisoquine hydroxylation phenotypes were determined twice in 15 Spanish healthy... more 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.
Clinical pharmacology and therapeutics, 1993
Debrisoquin and S-mephenytoin hydroxylation phenotypes were determined in 72 Spanish psychiatric ... more Debrisoquin and S-mephenytoin hydroxylation phenotypes were determined in 72 Spanish psychiatric patients treated with neuroleptic or antidepressant agents. One patient (1.4%) was classified as a poor metabolizer of S-mephenytoin. Between both neuroleptic-and antidepressant-treated patients, the distribution of the debrisoquin metabolic ratio was shifted toward higher values compared with 54 drugfiee healthy subjects. Forty percent of patients treated with neuroleptics and 5% of patients treated with antidepressants were classified as poor metabolizers of debrisoquin. CTP2D6 genotype analysis in 36 neuroleptic-treated patients confirmed that the high metabolic ratios were attributable to inhibition of CYP2D6 and not to overrepresentation of subjects with poor metabolizer genotypes. In 48 selected Spanish drug-fiee subjects, CTP2D6 genotype predicted the phenotype with 95% accuracy. Neuroleptics and antidepressants interfere at therapeutic doses with phenotyping for CYP2D6 but not for S-mephenytoin hydroxylation capacity. In psychotropic-treated patients, genotyping provides a valuable tool for prediction of the CYP2D6 phenotype. (CLIN PHARMACOL THER 1993;54:606-11.) There are two established polymorphisms of drug oxidation, the debrisoquin-sparteine and the S-mephenytoin hydroxylation polymorphisms. Subjects with deficient metabolism are classified as poor metabolizers, whereas the remainder are extensive metabolizers. About 7% of white subjects are poor metabolizers of debrisoquin, whereas 3% are poor metabolizers of S-mephenytoin.' The poor metabolizer phenotype of
British journal of clinical pharmacology, 1994
A large interindividual variability has previously been demonstrated in the bioavailability, stea... more A large interindividual variability has previously been demonstrated in the bioavailability, steady-state plasma concentrations and clearance of clozapine, an atypical neuroleptic drug. To evaluate the importance of genetic factors in the metabolism of clozapine, its disposition after a single oral dose of 10 mg was studied in 15 healthy Caucasian volunteers. Five of the subjects were poor metabolisers (PM) of debrisoquine, five were PM of S-mephenytoin, and the remaining five were extensive metabolisers (EM) of both probe drugs. There was a 10-fold interindividual variation in Cmax and a 14-fold variation in AUC(0, 24) of clozapine among the 15 subjects studied. The mean (s.d.) Cmax was 117 (81) nmol 1-1 and the mean AUC(0,24) value was 890 (711) nmol 1-1 h. The value of t,,z varied 3-fold with a mean (s.d.) of 13.3 (5.0) h. There were no significant differences in the plasma concentrations or any of the pharmacokinetic parameters of clozapine between PM and EM of debrisoquine, or between the two S-mephenytoin hydroxylation phenotypes. We conclude that neither of the major genetic polymorphisms of oxidative drug metabolism contribute to the large interindividual variability in clozapine pharmacokinetics.
British journal of clinical pharmacology, 1994
British journal of clinical pharmacology, 1994
In a previous study we showed that the disposition of clozapine after a single oral dose is unrel... more In a previous study we showed that the disposition of clozapine after a single oral dose is unrelated to either debrisoquine or S-mephenytoin hydroxylation polymorphism. The same 14 healthy subjects studied in that investigation were given 150 mg of caffeine. The reciprocal of plasma clozapine AUC (0,24), was correlated with an index of the N3-demethylation of caffeine (r, = 0.84; P = 0.0024), used as a measure of cytochrome P4501A2 (CYP1A2) activity. Ni-and N7-demethylation indices of caffeine also reflect CYP1A2 activity and were also correlated with clozapine clearance (rs = 0.89 and 0.85; P = 0.0013 and 0.0023; respectively). No significant relationships with xanthine oxidase and N-acetyl transferase activity, also assessed by a caffeine test, were found. This study suggests that clozapine is metabolised by CYP1A2 to a major extent.