Ten percent of North Spanish individuals carry duplicated or triplicated CYP2D6 genes associated with ultrarapid metabolism of debrisoquine.
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Adult↗
Biomedical subjects
L Bertilsson
Publications and source records attributed to L Bertilsson.
Decreased capacity for debrisoquine metabolism among black Tanzanians: analyses of the CYP2D6 genotype and phenotype.
The cytochrome P450 2D6 (CYP2D6) genotypes and phenotypes of 106 unrelated, healthy black Tanzanians of Bantu origin were investigated. The results revealed a population with a generally decreased capacity to metabolize the CYP2D6 substrate debrisoquine with 59% of the Tanzanian extensive metabolisers having debrisoquine metabolic ratios (MRs) > 1 versus 20% in Caucasians. This decrease in metabolic capacity was not fully explained by the partially or fully detrimental CYP2D6 gene mutations analysed for in this study. As many as 7% poor metabolizers of debrisoquine were identified but none was homozygous for defective CYP2D6 alleles. The majority among the group of poor metabolizers had relatively low metabolic ratios. The mutational profile indicated a closer association of the Tanzanian CYP2D locus to that of Zimbabweans rather than to that of Ethiopians. The defective alleles CYP2D6*3, *4, *5 and *6 were found at low frequencies (0%, 1%, 6%, 0%, respectively), whereas the CYP2D6*17 allele causing an enzyme with altered specificity was common (allele frequency = 17%). It is concluded that the CYP2D6 genotype in the Tanzanian Bantu population is different from that of other African populations examined to date and that further studies are required to explain the generally lower capacity to metabolize CYP2D6 substrates.
Base Sequence↗
Rapid high-performance liquid chromatographic method for determination of debrisoquine and 4-hydroxy-debrisoquine in urine for CYP2D6 phenotyping.
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Chromatography, High Pressure Liquid↗
10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes.
OBJECTIVE: To investigate the disposition and effects of nortriptyline and its major metabolite 10-hydroxy-nortriptyline line in panels of white subjects with different CYP2D6 genotypes, including those with duplicated and multiduplicated CYP2D6*2 genes and to evaluate the contribution of the number of functional C gamma P2D6 alleles to the metabolism of nortriptyline, used here as a model drug for CYP2D6 substrates. METHODS: Oral single doses of 25 to 50 mg nortriptyline were given to five poor metabolizers of debrisoquin (INN; debrisoquine) with no functional CYP2D6 gene, five extensive metabolizers with one functional CY2D6 gene, five extensive metabolizers with two functional CYP2D6 genes, five ultrarapid metabolizers with duplicated CYP2D6*2 genes, and one ultrarapid metabolizer with 13 copies of the CYP2D6*2 gene. Plasma kinetics of nortriptyline and 10-hydroxynortriptyline were analyzed. Anticholinergic effects (inhibition of salivation and accommodation disturbances), sedation, blood pressure, and effect on supine and erect pulse rate were measured. RESULTS: There was a clear relation between the C gamma P2D6 genotype and the plasma kinetics of nortriptyline and 10-hydroxynortriptyline. The proportion between the apparent oral clearances of nortriptyline in the groups with 0, 1, 2, 3, and 13 functional genes was 1:1:4:5:17. The proportions between AUC(nortriptyline) to AUC(10-hydroxynortriptyline) ratios in the groups with 0, 1, 2, 3, and 13 functional genes were 36:25:10:4:1. Oral plasma clearance of nortriptyline and AUC(nortriptyline) to AUC(10-hydroxynortriptyline) ratio both correlated significantly with the debrisoquin metabolic ratio (rS = -0.89, p = 0.0001; rS = 0.92, p = 0.0001). Although ultrarapid metabolizer subjects were given double the nortriptyline dose (50 mg), inhibition of salivation was not more pronounced compared with the other genotype groups given 25 mg nortriptyline. CONCLUSION: The results of this study show the quantitative importance of the CYP2D6 genotype, especially the presence of multiple functional CYP2D6 genes for the pharmacokinetics of nortriptyline and 10-hydroxynortriptyline. Genotyping of subjects with multiple copies of functional genes may be of great value for differentiating ultrarapid metabolizers from patients who do not comply with the prescription and for assuring adequate drug choice and dosage for these patients.
Analysis of Variance↗
Pharmacokinetics of nortriptyline and its 10-hydroxy metabolite in Chinese subjects of different CYP2D6 genotypes.
OBJECTIVES: To study the impact of the CYP2D6*10 allele on the disposition of nortriptyline in Chinese subjects. METHODS: A single dose of 25 mg nortriptyline was given orally to 15 healthy Chinese volunteers who were classified as extensive metabolizers after phenotyping with debrisoquin (INN, debrisoquine) and who were genotyped by allele-specific polymerase chain reaction. Five subjects were homozygous for CYP2D6*1, 5 subjects were homozygous for CYP2D6*10, and 5 subjects were heterozygous for these 2 alleles. Plasma concentrations of nortriptyline and its main metabolite 10-hydroxynortriptyline were measured by liquid chromatography-mass spectrometry, and the pharmacokinetics were studied during 168 hours after the dose. RESULTS: Subjects who were homozygous for CYP2D6*10 had significantly higher total areas under the plasma concentration-time curve (AUC), lower apparent oral clearances, and longer mean plasma half-life of nortriptyline than subjects in the CYP2D6*1/*1 and the heterozygous groups. For 10-hydroxynortriptyline, the AUC was lower and the plasma half-life was longer in subjects who were homozygous for CYP2D6*10 than in subjects in the other 2 groups. CONCLUSION: The CYP2D6*10 allele in Chinese subjects was associated with significantly higher plasma levels of nortriptyline compared with the CYP2D6*1 allele because of an impaired metabolism of nortriptyline to 10-hydroxynortriptyline, particularly in the subjects with the CYP2D6*10/*10 genotype. The results suggest that genotyping of CYP2D6 may be a useful tool in predicting the pharmacokinetics of nortriptyline.
Adult↗
Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype.
OBJECTIVE: To investigate the CYP2C19 polymorphism in Tanzanians because this enzyme shows large interindividual differences in activity and metabolizes several drugs of importance in Africa, especially the antimalarial agent chloroguanide (INN, proguanil). METHODS: Two hundred fifty-one Tanzanian healthy volunteers were phenotyped with respect to CYP2C19 with use of a single oral dose of mephenytoin (n = 106), a single oral dose of omeprazole (n = 207), or both. Sixty-two were phenotyped with both probe drugs. The urinary 0- to 8-hour S/R-mephenytoin ratio and the plasma omeprazole metabolic ratio (MR) (omeprazole/hydroxyomeprazole) 3 hours after drug intake were determined. The genotype was determined by analysis for CYP2C19*1 (wt), CYP2C19*2 (m1), and CYP2C19*3 (m2). Ten subjects with high omeprazole MR were screened for new mutations in the CYP2C19 gene by searching for single-strand conformation polymorphisms (SSCP). RESULTS: Eight subjects were classified as mephenytoin poor metabolizers (7.5%). Only 5 of these were homozygous for mutated alleles. The S/R ratio was skewed to the right (lower CYP2C19 activity) compared with other ethnic groups studied previously. No new mutations were found with polymerase chain reaction (PCR)-SSCP. We found 30 volunteers (14.5%) with an MR > 7, which is the antimode found previously in white subjects and Asian subjects. Of the 251 volunteers genotyped, 3.2% were homozygous for mutated alleles and 66.1% were homozygous for the wild-type allele. The allele frequencies of CYP2C19*1, *2, and *3 were 81.5%, 17.9%, and 0.6%, respectively. The correlation between the S/R-mephenytoin ratio and the omeprazole MR was significant (Spearman r = 0.59; P < .01). CONCLUSION: Tanzanians have a decreased capacity to metabolize both omeprazole and mephenytoin when their genotype is compared with metabolic capacity and genotype in other previously studied populations. We identified a low frequency of the Asian allele (CYP2C19*3). Although we did not find any new mutations, our results may be consistent with the presence of yet-unidentified mutations of CYP2C19 that causes decreased CYP2C19 activity in the Tanzanian population.
Administration, Oral↗
CYP2D6 polymorphism is not crucial for the disposition of selegiline.
OBJECTIVE: To determine the possible impact of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of selegiline. METHODS: Five poor metabolizers and 8 extensive metabolizers of debrisoquin (INN, debrisoquine) were given 10 mg selegiline hydrochloride. The concentrations of selegiline and its main metabolites in serum were determined for 4 days. The pharmacodynamics were quantitated by measuring platelet monoamine oxidase type B activity for 3 weeks. In addition, the effect of selegiline and its main metabolites on the CYP2D6-catalyzed dextromethorphan O-demethylase activity and the effect of quinidine on the metabolism of selegiline were studied in human liver microsomes. RESULTS: Peak serum concentrations of selegiline were reached rapidly and ranged from 1 to 32 nmol/L. The metabolite concentrations were considerably higher and remained so for a longer period. There were no significant differences in the pharmacokinetic parameters of selegiline, desmethylselegiline, and l-amphetamine between poor metabolizers and extensive metabolizers. However, the area under the serum concentration-time curve (AUC) values of l-methamphetamine were, on average, 46% higher (P = .01) in poor metabolizers than in extensive metabolizers. No significant correlations were found between debrisoquin metabolic ratio and AUC values of selegiline or its metabolites, except for l-methamphetamine (rs = 0.90; P < .001). The maximum monoamine oxidase type B inhibition was 97% in both groups. The inhibitory potency of selegiline, desmethylselegiline, and l-methamphetamine toward dextromethorphan O-demethylase was very low (50% inhibitory concentration values from 160 to 580 mumol/L). Quinidine (< or = 100 mumol/L) did not inhibit the formation of desmethylselegiline or l-methamphetamine from selegiline. CONCLUSIONS: CYP2D6 is not important in the primary elimination of selegiline, and the biological effect of selegiline seems to be similar in poor metabolizers and extensive metabolizers of debrisoquin. The inhibitory effect of selegiline and its main metabolites on CYP2D6 activity seems to be negligible.
Adrenergic Agents↗
Influence of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamic of tolterodine.
OBJECTIVE: To determine whether cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of tolterodine by investigating potential differences in pharmacokinetics and pharmacodynamic (heart rate, accommodation, and salivation) of tolterodine and its 5-hydroxymethyl metabolite between poor metabolizers and extensive metabolizers of debrisoquin (INN, debrisoquine). METHODS: Sixteen male subjects (eight extensive metabolizers and eight poor metabolizers) received 4 mg tolterodine by mouth twice a day for 8 days followed by a single intravenous infusion of 1.8 mg tolterodine for 30 minutes after a washout period. Doses were given as the tartrate salt. The pharmacokinetics of tolterodine and 5-hydroxymethyl metabolite were determined, and the pharmacodynamic were measured. RESULTS: The mean systemic clearance of tolterodine was significantly lower (p < 0.001) among poor metabolizers (9.0 +/- 2.1 l/hr) compared with extensive metabolizers (44 +/- 13 L/hr), resulting in a fourfold longer elimination half-life (p < 0.001). The terminal half-life of the 5-hydroxymethyl metabolite (2.9 +/- 0.4 hours) was slightly longer than that of the parent compound (2.3 +/- 0.6 hours) among extensive metabolizers, but the 5-hydroxymethyl metabolite was undetectable in the serum of poor metabolizers. Only minor differences in pharmacodynamic effects after tolterodine dosage were observed between the groups. Tolterodine caused a similar decrease in salivation in both panels. The decrease occurred when the concentration of unbound tolterodine and 5-hydroxymethyl metabolite among extensive metabolizers was comparable with that of tolterodine among poor metabolizers. CONCLUSIONS: Tolterodine is extensively metabolized by CYP2D6 with high specificity. Despite the effect on pharmacokinetics, the CYP2D6 polymorphism does not appear to be of great importance in the antimuscarinic effect, probably because of the additive action of parent drug and active metabolite.
Administration, Oral↗
Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors.
BACKGROUND: Potential drug-drug interactions can be identified in vitro by exploring the importance of specific cytochrome P450 (CYP) isozymes for drug metabolism. The metabolism of the local anesthetic ropivacaine to 3-hydroxyropivacaine and (S)-2',6'-pipecoloxylidide was shown in vitro to be dependent on CYP1A2 and 3A4, respectively. In this in vivo model study we quantitated the role of these 2 isozymes for the metabolism of ropivacaine. METHODS: In a randomized, 3-way crossover study, 12 healthy subjects received a single dose of 40 mg ropivacaine intravenously alone or combined either with 25 mg fluvoxamine as a CYP1A2 inhibitor or with 100 mg ketoconazole as a CYP3A4 inhibitor twice daily for 2 days. Venous plasma and urine samples were collected over 10 hours and 24 hours, respectively. The samples were analyzed for ropivacaine base, 3-hydroxyropivacaine, and (S)-2',6'-pipecoloxylidide. RESULTS: Coadministration with fluvoxamine decreased the mean total plasma clearance of ropivacaine from 354 to 112 mL/min (68%), whereas ketoconazole decreased plasma clearance to 302 mL/min (15%). The relative changes in unbound plasma clearance were similar to the changes in total plasma clearance. The ropivacaine half-life (t1/2) of 1.9 hours was almost doubled during fluvoxamine administration and the plasma concentration at the end of infusion increased slightly, whereas the corresponding parameters after ketoconazole administration remained unchanged. Coadministration with ketoconazole almost abolished the (S)-2',6'-pipecoloxylidide concentrations in plasma, whereas fluvoxamine administration increased the (S)-2',6'-pipecoloxylidide levels. The fraction of dose excreted as 3-hydroxyropivacaine in urine decreased during fluvoxamine administration from 39% to 13%. CONCLUSIONS: CYP1A2 is the most important isozyme for the metabolism of ropivacaine. Drug-drug interactions with strong inhibitors of this isozyme could be of clinical relevance during repeated administration. A potent inhibitor of CYP3A4 causes a minor decrease in clearance, which should be of no clinical relevance.
Adult↗
Artemisinin induces omeprazole metabolism in human beings.
OBJECTIVE: This study investigated whether time-dependent artemisinin pharmacokinetics correlated to CYP3A4 or CYP2C19 activity in vivo. METHODS: Artemisinin (two oral doses per day of 250 mg) was given to nine healthy Vietnamese subjects for 7 days (day 1 to day 7). Single 20 mg doses of omeprazole were given orally on day -7, day 1, and day 7. Single doses of artemisinin and omeprazole were given in combination on day 14 after a 6-day washout period. The pharmacokinetics of artemisinin, omeprazole, hydroxyomeprazole, and omeprazole sulfone were evaluated on days -7, 1, 7, and 14. On the same days urine was collected for the determination of 6beta-hydroxycortisol and cortisol excretion. RESULTS: Areas under plasma concentration-time curves (AUC) for artemisinin and omeprazole decreased on day 7 to 20% (95% confidence intervals, 13%, 28%) and 35% (25%, 46%), respectively, compared with values on day 1. AUC ratios for hydroxyomeprazole/omeprazole increased 2.2-fold (1.7, 2.7) on day 7 compared with values on day 1. All values were normalized at day 14. There were no significant changes in the omeprazole sulfone/omeprazole ratio or in the 6beta-hydroxycortisol/cortisol ratio between the study days. In one subject found to have poor CYP2C19 metabolization, the elimination of omeprazole increased after artemisinin exposure, with no change in the hydroxyomeprazole/omeprazole AUC ratio. CONCLUSION: Artemisinin did not alter CYP3A4 activity, whereas an increase in CYP2C19 activity was observed. The increased elimination of omeprazole in both poor and extensive CYP2C19 metabolizers suggests artemisinin induces both CYP2C19 and another enzyme.
2-Pyridinylmethylsulfinylbenzimidazoles↗
CYP2C19 genotype and phenotype determined with omeprazole in patients with acid-related disorders with and without Helicobacter pylori infection.
BACKGROUND: Omeprazole is to a major extent metabolized by cytochrome P450 isozyme CYP2C19. The aims of this study were to compare the phenotype of CYP2C19 determined by omeprazole with the genotype and to determine the effect of Helicobacter pylori infection on the metabolism of omeprazole. METHODS: One-hundred and forty-three Caucasian patients with acid-related disorders assessed with a combination of gastrointestinal symptoms and upper endoscopic findings were given 20 mg omeprazole orally. Three hours after intake, omeprazole and 5-hydroxyomeprazole plasma concentrations were determined with high-performance liquid chromatography, and the phenotype for metabolic capacity was expressed as metabolic ratio (MR). Genotyping of defect alleles (CYP2C19*2 and *3) was performed by polymerase chain reaction amplification. One hundred eleven patients were tested after the first dose of omeprazole and 32 patients after repetitive administration (median time, 30 days). H. pylori serology was determined with enzyme-linked immunosorbent assay at the time of phenotyping. RESULTS: Genotypically, 2.8% had two mutated alleles and were poor metabolizers (PM), and 22.4% were heterozygous extensive metabolizers (EM). Among the 111 patients who received the first omeprazole dose, 4 patients had MR >5--that is, belonged to the PM phenotype. Two of these had PM genotype (both CYP2C19*2/*2), and two had an EM genotype (CYP2C19*11*1 and *1/*3), indicating that they have still unidentified mutations. In the heterozygous EM group the mean MR was higher in patients who had been on continued omeprazole treatment than in those given the first dose (5.7 versus 2.5, P = 0.02). There were no significant differences in MR and omeprazole concentrations between H. pylori-negative (43%) and -positive (57%) patients. CONCLUSION: In all but two patients with probable unidentified mutations there was agreement between the CYP2C19 phenotype determined by omeprazole and the genotype. The metabolism of omeprazole in patients with acid-related disorders is genetically determined and without relation to H. pylori infection.
Anti-Ulcer Agents↗
1- and 3-hydroxylations, in addition to 4-hydroxylation, of debrisoquine are catalyzed by cytochrome P450 2D6 in humans.
Twenty-one healthy Swedish Caucasian volunteers, representing different groups with 0-13 functional cytochrome P450 (CYP) 2D6 genes, were given a single oral dose of 20 mg of debrisoquine. The hypothesis of further oxidation of the main metabolite, (S)-4-hydroxydebrisoquine, in subjects with multiple CYP2D6 genes was tested by screening the 0-8-hr urine samples for dihydroxylated metabolites of debrisoquine with protonated molecular ions at m/z 208, using LC/MS. Three peaks were detected in a subject with 13 functional CYP2D6 genes. One compound was identified as dihydroxylated debrisoquine (presumably with hydroxylation at position 4 plus one of the positions in the aromatic ring). This metabolite had not been previously demonstrated in humans and was detected only in this subject. The other two compounds, which were measurable in various amounts in all subjects investigated, were identified as 2-(guanidinomethyl)phenylacetic acid and 2-(guanidinoethyl)benzoic acid. They had been previously detected in the urine of humans, dogs, and rats. They were distinguished by acid-catalyzed deuterium exchange of the hydrogens at the alpha-position, with respect to the carboxylic acid group, of the former but not the latter acid. The acids are formed by 3- and 1-hydroxylation of debrisoquine, respectively, followed by ring opening to aldehydes, which are further oxidized to acids. Strong Spearman rank correlations between debrisoquine products of 1- or 3-hydroxydebrisoquine and debrisoquine/4-hydroxydebrisoquine ratios (rS = 0.97 and rS = 0.96, respectively), using the intensity of the peaks of the reconstructed ion-current chromatograms, clearly showed that both hydroxylation steps are catalyzed by CYP2D6. Because reference compounds for the two acids were not available, the absolute quantities could not be determined.
Antihypertensive Agents↗
Enantioselective hydroxylation of omeprazole catalyzed by CYP2C19 in Swedish white subjects.
Stereoselective disposition of omeprazole and its formed 5-hydroxy metabolite were studied in five poor metabolizers and five extensive metabolizers of S-mephenytoin. After a single oral dose of omeprazole (20 mg), the plasma concentrations of the separate enantiomers of the parent drug and the 5-hydroxy metabolite were determined for 10 hours after drug intake. In poor metabolizers, the area under the plasma concentration versus time curve [AUC(0-8)] of (+)-omeprazole was larger and that of the 5-hydroxy metabolite of this enantiomer was smaller than the AUC(0-8) values in extensive metabolizers (p < 0.001). The mean AUC(0-8) of the (-)-enantiomer of omeprazole was also higher in poor metabolizers than in extensive metabolizers, but only 3.1-fold compared with 7.5-fold for (+)-omeprazole. The rate of formation of the hydroxy metabolite from (-)-omeprazole was low and not significantly different in poor and extensive metabolizers. These results show that (+)-omeprazole is to a major extent hydroxylated by CYP2C19. Also (-)-omeprazole may partly be metabolized by this enzyme but is mainly metabolized by another enzyme, presumably CYP3A4, to the achiral sulfone metabolite. The plasma concentration ratio of omeprazole to 5-hydroxyomeprazole obtained 3 hours after the drug intake has been used to distinguish between extensive and poor metabolizer phenotypes. With use of the ratio between the (+)-enantiomers of the parent drug and the metabolite, a better discrimination between phenotypes was obtained. The ratio between the (-)-enantiomers also separated the phenotypes but was less discriminatory. For the future, measurement of total concentrations will suffice for phenotyping.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Inhibition of the sulfoxidation of omeprazole by ketoconazole in poor and extensive metabolizers of S-mephenytoin.
BACKGROUND: The metabolism of omeprazole includes hydroxylation catalyzed by CYP2C19 and, to a minor extent, sulfoxidation, presumably by CYP3A4. Sulfoxidation may be the predominant pathway in individuals devoid of the genetically determined CYP2C19 activity. Ketoconazole is a known CYP3A4 inhibitor in daily doses from 200 to 400 mg. In this study ketoconazole was used as a probe to investigate the extent to which CYP3A4 is involved in omeprazole metabolism in vivo. METHODS: A single oral 20 mg dose of omeprazole before and after four daily doses of 200, 100, or 50 mg ketoconazole was given to 10 healthy subjects, previously phenotyped as poor or extensive metabolizers of S-mephenytoin. Concentrations of omeprazole, 5-hydroxyomeprazole, omeprazole sulfone, and ketoconazole were analyzed with reversed-phase HPLC methods in plasma samples collected repeatedly for 12 hours after dosing. RESULTS: After intake of 20 mg omeprazole with 0, 50, 100, and 200 mg ketoconazole, mean values for omeprazole sulfone area under the plasma concentration versus time curve from 0 to 6 hours [AUC(0-6)] were 482, 206, 167, and < 100 nmol/L.hr in extensive metabolizers and 3160, 2430, 937, and 534 nmol/L.hr in poor metabolizers, respectively. Mean omeprazole AUC(0-6) increased from 1660 to 2265 nmol/L.hr in extensive metabolizers and from 7715 to 15319 nmol/L.hr in poor metabolizers after intake of 200 mg ketoconazole. CONCLUSIONS: An oral daily dose of 100 to 200 mg ketoconazole is sufficient to provide a marked inhibition of the formation of the omeprazole sulfone in both extensive and poor metabolizers and leads to a doubling of omeprazole levels in poor metabolizers, whereas 50 mg ketoconazole provides only partial inhibition. We concluded that CYP3A4 catalyzes the sulfoxidation of omeprazole and that this is the predominant metabolic pathway of omeprazole in poor metabolizers of S-mephenytoin.
Adult↗
Carbamazepine treatment induces the CYP3A4 catalysed sulphoxidation of omeprazole, but has no or less effect on hydroxylation via CYP2C19.
AIMS: Omeprazole has been shown previously to be metabolized by the two cytochrome P450 isoforms CYP2C19 (hydroxylation) and CYP3A4 (sulphoxidation). The objective of this study was to test the inducibility of these enzymes by carbamazepine (CBZ). METHODS: Omeprazole was given as a single oral dose before and after 3 weeks of treatment of five patients with CBZ (400-600 mg daily). RESULTS: Mean area under the plasma concentration vs time curve (AUC) between 0 and 8 h after drug intake, decreased by about 40% for omeprazole and its hydroxy metabolite and increased for its sulphone metabolite, but the changes were not statistically significant. The ratio of the AUCs of omeprazole and its sulphone, used as an index of CYP3A4 activity, decreased in all patients (P = 0.052), while there was no change in the omeprazole/hydroxyomeprazole AUC ratio used as an index for CYP2C19 activity. There was a significant decrease in the mean ratio of the AUC of the hydroxy and sulphone metabolites from 2.58 to 0.93 (P = 0.046) with a mean difference of 1.79 (95% CI: 0.07 to 3.50) showing that the induction was more pronounced for CYP3A4 than for CYP2C19. CONCLUSIONS: CBZ induces CYP3A4, but not, or to a lesser extent, CYP2C19. The induction of the sulphoxidation of omeprazole by CBZ seems to have no major clinical implication.
Adult↗
The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine.
AIMS: Clozapine (CLZ), an atypical neuroleptic with a high risk of causing agranulocytosis, is metabolized in the liver to desmethylclozapine (DCLZ) and clozapine N-oxide (CLZ-NO). This study investigated the involvement of different CYP isoforms in the formation of these two metabolites. METHODS: Human liver microsomal incubations, chemical inhibitors, specific antibodies, and different cytochrome P450 expression systems were used. RESULTS: Km and Vmax values determined in human liver microsomes were lower for the demethylation (61 +/- 21 microM, 159 +/- 42 pmol min(-1) mg protein(-1) mean +/- s.d.; n = 4), than for the N-oxidation of CLZ (308 +/- 1.5 microM, 456 +/- 167 pmol min(-1) mg protein(-1); n = 3). Formation of DCLZ was inhibited by fluvoxamine (53 +/- 28% at 10 microM), triacetyloleandomycin (33 +/- 15% at 10 microM), and ketoconazole (51 +/- 28% at 2 microM) and by antibodies against CYP1A2 and CYP3A4. CLZ-NO formation was inhibited by triacetyloleandomycin (34 +/- 16% at 10 microM) and ketoconazole (51 +/- 13% at 2 microM), and by antibodies against CYP3A4. There was a significant correlation between CYP3A content and DCLZ formation in microsomes from 15 human livers (r=0.67; P=0.04). A high but not significant correlation coefficient was found for CYP3A content and CLZ-NO formation (r=0.59; P=0.09). Using expression systems it was shown that CYP1A2 and CYP3A4 formed DCLZ and CLZ-NO. Km and Vmax values were lower in the CYP1A2 expression system compared to CYP3A4 for both metabolic reactions. CONCLUSIONS: It is concluded that CYP1A2 and CYP3A4 are involved in the demethylation of CLZ and CYP3A4 in the N-oxidation of CLZ. Close monitoring of CLZ plasma levels is recommended in patients treated at the same time with other drugs affecting these two enzymes.
Antibodies↗
The CYP2D6 genotype and plasma concentrations of mianserin enantiomers in relation to therapeutic response to mianserin in depressed Japanese patients.
The relationship between therapeutic response to racemic mianserin and steady-state plasma concentrations of S(+)- and R(-)-mianserin was studied in 26 Japanese patients with major depression. The daily dose of mianserin was 30 mg, and the duration of treatment was 3 weeks. Regarding S-mianserin, the proportion of responders (final Montgomery-Asberg Depression Rating Scale score of 10 or less) was significantly higher in the plasma concentration range of 10 to 23 ng/mL than outside (10 of 11 vs. 3 of 15, p = 0.0005). Such a plasma concentration difference between responders and nonresponders was not found for R-mianserin. In 15 patients, the relationships between the CYP2D6 genotype, determined by allele-specific polymerase chain reaction analysis and Escherichia coli RI restriction fragment length polymorphism, plasma concentrations of the enantiomers, and the therapeutic response were studied. Five patients were homozygous for the wild type (wt) allele (wt/wt), nine were heterozygous for the CYP2D6Ch (Ch) allele causing decreased CYP2D6 activity (Ch/wt), and one patient was heterozygous for the Ch allele and the defect allele CYP2D6D (D) (Ch/D). The Ch/wt group showed significantly higher plasma concentrations of S-mianserin (mean +/- SD: 15 +/- 6 vs. 8 +/- 1 ng/mL, p = 0.007) and proportion of responders (8 of 9 vs. 1 of 5, p = 0.023) than the wt/wt group. The patient with the Ch/D genotype had the highest plasma concentration of S-mianserin (37 ng/mL) and a poor response. No significant relationship was found between the CYP2D6 genotype and plasma concentration of R-mianserin. The study presented here thus suggests that the CYP2D6 genotype plays a major role in controlling plasma concentration of the S-enantiomer of mianserin, which contributes to a major extent to the antidepressant effect during mianserin treatment.
Adult↗
An S-mephenytoin cysteine conjugate identified in urine of extensive but not of poor metabolizers of S-mephenytoin.
A conjugate of S-mephenytoin excreted in urine of extensive but not of poor metabolizers of S-mephenytoin has previously been reported. This conjugate, which is easily hydrolysed back to S-mephenytoin, has now been isolated and identified in urine from one extensive metabolizer after a single dose of 100 mg racemic mephenytoin. High performance liquid chromatography purification, followed by gas chromatographic, mass spectrometric and amino acid analyses showed that the isolated compound is a cysteine conjugate of S-mephenytoin. The significant mass spectrometric ions have been confirmed in three additional extensive metabolizers of S-mephenytoin, but were not detectable in urine from three poor metabolizer subjects. The exact structure of the conjugate is unknown, but we suggest that an S-N bond between cysteine and S-mephenytoin is formed via an oxidative radical mechanism catalyzed by CYP2C19.
Chromatography, High Pressure Liquid↗